Aqueous pharmaceutical formulation of hydrocortisone sodium phosphate and monothioglycerol

ABSTRACT

Aqueous hydrocortisone sodium phosphate and monothioglycerol formulations are disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of International Patent ApplicationNo. PCT/US2021/051349 filed Sep. 21, 2021, which claims the benefit ofU.S. Provisional Patent Application No. 63/081,164, filed Sep. 21, 2020,each of which is incorporated by reference herein in its entirety.

FIELD

The invention relates generally to hydrocortisone and hydrocortisoneprodrugs, and pharmaceutically acceptable salts thereof, and relatedformulations.

BACKGROUND

Hydrocortisone is the name for the hormone cortisol when supplied as amedication. It is used in oral administration, intravenous injection, ortopical application. It is used as an immunosuppressive drug, given byinjection in the treatment of severe allergic reactions such asanaphylaxis and angioedema. It may be used topically for allergicrashes, eczema, psoriasis, itching and other inflammatory skinconditions.

Therapeutic hydrocortisone is a synthetic or semisynthetic analog ofnatural hydrocortisone hormone produced by the adrenal glands withprimary glucocorticoid and minor mineralocorticoid effects. As aglucocorticoid receptor agonist, hydrocortisone promotes proteincatabolism, gluconeogenesis, capillary wall stability, renal excretionof calcium, and suppresses immune and inflammatory responses.

SUMMARY

The disclosure provides an aqueous pharmaceutical formulation comprisingfrom about 50 to about 150 mg/mL hydrocortisone sodium phosphate, fromabout 2.5 to about 12.5 mg/mL monothioglycerol, and water. In someembodiments, the formulation comprises from about 50 to about 60 mg/mLhydrocortisone sodium phosphate, from about 60 to about 70 mg/mLhydrocortisone sodium phosphate, or from about 70 to about 80 mg/mLhydrocortisone sodium phosphate. In some embodiments, the formulationcomprises from about 60 to about 65 mg/mL hydrocortisone sodiumphosphate, or from about 65 to about 70 mg/mL hydrocortisone sodiumphosphate. In some embodiments, the formulation comprises from about 120to about 130 mg/mL hydrocortisone sodium phosphate, from about 130 toabout 140 mg/mL hydrocortisone sodium phosphate, or from about 140 toabout 150 mg/mL hydrocortisone sodium phosphate. In some embodiments,the formulation comprises from about 130 to about 135 mg/mLhydrocortisone sodium phosphate, or from about 135 to about 140 mg/mLhydrocortisone sodium phosphate. In some embodiments, the formulationcomprises about 50 mg/mL hydrocortisone sodium phosphate, about 55 mg/mLhydrocortisone sodium phosphate, about 60 mg/mL hydrocortisone sodiumphosphate, about 65 mg/mL hydrocortisone sodium phosphate, about 70mg/mL hydrocortisone sodium phosphate, about 75 mg/mL hydrocortisonesodium phosphate, about 80 mg/mL hydrocortisone sodium phosphate, about85 mg/mL hydrocortisone sodium phosphate, about 90 mg/mL hydrocortisonesodium phosphate, about 95 mg/mL hydrocortisone sodium phosphate, about100 mg/mL hydrocortisone sodium phosphate, about 105 mg/mLhydrocortisone sodium phosphate, about 110 mg/mL hydrocortisone sodiumphosphate, about 115 mg/mL hydrocortisone sodium phosphate, about 120mg/mL hydrocortisone sodium phosphate, about 125 mg/mL hydrocortisonesodium phosphate, about 130 mg/mL hydrocortisone sodium phosphate, about135 mg/mL hydrocortisone sodium phosphate, about 140 mg/mLhydrocortisone sodium phosphate, about 145 mg/mL hydrocortisone sodiumphosphate, or about 150 mg/mL hydrocortisone sodium phosphate. In someembodiments, the formulation comprises about 60 mg/mL hydrocortisonesodium phosphate, about 61 mg/mL hydrocortisone sodium phosphate, about62 mg/mL hydrocortisone sodium phosphate, about 63 mg/mL hydrocortisonesodium phosphate, about 64 mg/mL hydrocortisone sodium phosphate, about65 mg/mL hydrocortisone sodium phosphate, about 66 mg/mL hydrocortisonesodium phosphate, about 67 mg/mL hydrocortisone sodium phosphate, about68 mg/mL hydrocortisone sodium phosphate, about 69 mg/mL hydrocortisonesodium phosphate, or about 70 mg/mL hydrocortisone sodium phosphate. Insome embodiments, the formulation comprises about 67 mg/mLhydrocortisone sodium phosphate, about 67.1 mg/mL hydrocortisone sodiumphosphate, about 67.2 mg/mL hydrocortisone sodium phosphate, about 67.3mg/mL hydrocortisone sodium phosphate, about 67.4 mg/mL hydrocortisonesodium phosphate, about 67.5 mg/mL hydrocortisone sodium phosphate,about 67.6 mg/mL hydrocortisone sodium phosphate, about 67.7 mg/mLhydrocortisone sodium phosphate, about 67.8 mg/mL hydrocortisone sodiumphosphate, about 67.9 mg/mL hydrocortisone sodium phosphate, or about 68mg/mL hydrocortisone sodium phosphate. In some embodiments, theformulation comprises about 130 mg/mL hydrocortisone sodium phosphate,about 131 mg/mL hydrocortisone sodium phosphate, about 132 mg/mLhydrocortisone sodium phosphate, about 133 mg/mL hydrocortisone sodiumphosphate, about 134 mg/mL hydrocortisone sodium phosphate, about 135mg/mL hydrocortisone sodium phosphate, about 136 mg/mL hydrocortisonesodium phosphate, about 137 mg/mL hydrocortisone sodium phosphate, about138 mg/mL hydrocortisone sodium phosphate, about 139 mg/mLhydrocortisone sodium phosphate, or about 140 mg/mL hydrocortisonesodium phosphate. In some embodiments, the formulation comprises about134 mg/mL hydrocortisone sodium phosphate, about 134.1 mg/mLhydrocortisone sodium phosphate, about 134.2 mg/mL hydrocortisone sodiumphosphate, about 134.3 mg/mL hydrocortisone sodium phosphate, about134.4 mg/mL hydrocortisone sodium phosphate, about 134.5 mg/mLhydrocortisone sodium phosphate, about 134.6 mg/mL hydrocortisone sodiumphosphate, about 134.7 mg/mL hydrocortisone sodium phosphate, about134.8 mg/mL hydrocortisone sodium phosphate, about 134.9 mg/mLhydrocortisone sodium phosphate, or about 135 mg/mL hydrocortisonesodium phosphate.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate aqueous pharmaceutical formulation described herein, theformulation comprising from about 2.5 to about 3.5 mg/mLmonothioglycerol, from about 3.5 to about 4.5 mg/mL monothioglycerol,from about 4.5 to about 5.5 mg/mL monothioglycerol, from about 5.5 toabout 6.5 mg/mL monothioglycerol, from about 6.5 to about 7.5 mg/mLmonothioglycerol, from about 7.5 to about 8.5 mg/mL monothioglycerol,from about 8.5 to about 9.5 mg/mL monothioglycerol, from about 9.5 toabout 10.5 mg/mL monothioglycerol, from about 10.5 to about 11.5 mg/mLmonothioglycerol, or from about 11.5 to about 12.5 mg/mLmonothioglycerol. In some embodiments, the formulation comprises fromabout 4 to about 4.25 mg/mL monothioglycerol, from about 4.25 to about4.5 mg/mL monothioglycerol, from about 4.5 to about 4.75 mg/mLmonothioglycerol, from about 4.75 to about 5 mg/mL monothioglycerol,from about 5 to about 5.25 mg/mL monothioglycerol, from about 5.25 toabout 5.5 mg/mL monothioglycerol, from about 5.5 to about 5.75 mg/mLmonothioglycerol, or from about 5.75 to about 6 mg/mL monothioglycerol.In some embodiments, the formulation comprises from about 9 to about9.25 mg/mL monothioglycerol, from about 9.25 to about 9.5 mg/mLmonothioglycerol, from about 9.5 to about 9.75 mg/mL monothioglycerol,from about 9.75 to about 10 mg/mL monothioglycerol, from about 10 toabout 10.25 mg/mL monothioglycerol, from about 10.25 to about 10.5 mg/mLmonothioglycerol, from about 10.5 to about 10.75 mg/mL monothioglycerol,or from about 10.75 to about 11 mg/mL monothioglycerol. In someembodiments, the formulation comprises about 4.5 mg/mL monothioglycerol,about 4.6 mg/mL monothioglycerol, about 4.7 mg/mL monothioglycerol,about 4.8 mg/mL monothioglycerol, about 4.9 mg/mL monothioglycerol,about 5 mg/mL monothioglycerol, about 5.1 mg/mL monothioglycerol, about5.2 mg/mL monothioglycerol, about 5.3 mg/mL monothioglycerol, about 5.4mg/mL monothioglycerol, or about 5.5 mg/mL monothioglycerol. In someembodiments, the formulation comprises about 9.5 mg/mL monothioglycerol,about 9.6 mg/mL monothioglycerol, about 9.7 mg/mL monothioglycerol,about 9.8 mg/mL monothioglycerol, about 9.9 mg/mL monothioglycerol,about 10 mg/mL monothioglycerol, about 10.1 mg/mL monothioglycerol,about 10.2 mg/mL monothioglycerol, about 10.3 mg/mL monothioglycerol,about 10.4 mg/mL monothioglycerol, or about 10.5 mg/mL monothioglycerol.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, the formulation further comprising from about 0.5 toabout 2.5 mg/mL monobasic sodium phosphate.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, the formulation further comprising from about 5 toabout 25 mg/mL dibasic sodium phosphate.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, the formulation further comprising from about 0.1 toabout 1 mg/mL disodium EDTA.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein the pharmaceutical formulation has a pH fromabout 7.5 to about 9.5.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein the pharmaceutical formulation has a pH ofabout 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7,about, 8.8, about 8.9, or about 9.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein the formulation comprises from no impuritiesto less than, or no more than 0.05% impurities upon formulation.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein the formulation comprises from no impuritiesto less than, or no more than 0.07% impurities upon storage at 25° C.for about 3 months.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein upon storage at 25° C. for about 3 months, theformulation comprises from no impurities to less than, or no more than0.01% impurities, from no impurities to less than, or no more than 0.02%impurities, from no impurities to less than, or no more than 0.03%impurities, from no impurities to less than, or no more than 0.04%impurities, from no impurities to less than, or no more than 0.05%impurities, from no impurities to less than, or no more than 0.06%impurities, or from no impurities to less than, or no more than 0.07%impurities.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein the formulation comprises from no impuritiesto less than, or no more than 0.20% impurities upon storage at 25° C.for about 6 months.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein upon storage at 25° C. for about 6 months, theformulation comprises from no impurities to less than, or no more than0.1% impurities, from no impurities to less than, or no more than 0.11%impurities, from no impurities to less than, or no more than 0.12%impurities, from no impurities to less than, or no more than 0.13%impurities, from no impurities to less than, or no more than 0.14%impurities, from no impurities to less than, or no more than 0.15%impurities, from no impurities to less than, or no more than 0.16%impurities, from no impurities to less than, or no more than 0.17%impurities, from no impurities to less than, or no more than 0.18%impurities, from no impurities to less than, or no more than 0.19%impurities, or from no impurities to less than, or no more than 0.2%impurities.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein upon storage at 40° C. for about 1 month, theformulation comprises from no impurities to less than, or no more than0.35% impurities.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein upon storage at 40° C. for about 2 months, theformulation comprises from no impurities to less than, or no more than0.7% impurities.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein upon storage at 40° C. for about 3 months, theformulation comprises from no impurities to less than, or no more than1.5% impurities.

In some embodiments, the disclosure provides a hydrocortisone sodiumphosphate and monothioglycerol aqueous pharmaceutical formulationdescribed herein, wherein upon storage at 40° C. for about 6 months, theformulation comprises from no impurities to less than, or no more than2% impurities.

In one embodiment, the disclosure a pharmaceutical formulationcomprising hydrocortisone, a hydrocortisone prodrug, and/or apharmaceutically acceptable salt of any one thereof, and one or moreinactive ingredients. In some embodiments, the hydrocortisone prodrug isa hydrocortisone ester. In some embodiments, the hydrocortisone prodrugor pharmaceutically acceptable salt thereof is selected fromhydrocortisone sodium phosphate, hydrocortisone sodium succinate,hydrocortisone hydrogen succinate, hydrocortisone butyrate,hydrocortisone acetate. In some embodiments, the hydrocortisone prodrugor pharmaceutically acceptable salt thereof is hydrocortisone sodiumphosphate. In some embodiments, the concentration of hydrocortisonesodium phosphate in the pharmaceutical formulation is between about 5mg/mL and about 100 mg/mL. In some embodiments, the concentration ofhydrocortisone sodium phosphate in the pharmaceutical formulation isbetween about 50 mg/mL and about 100 mg/mL. In some embodiments, theconcentration of hydrocortisone sodium phosphate in the pharmaceuticalformulation is between about 25 mg/mL and about 75 mg/mL. In someembodiments, the concentration of hydrocortisone sodium phosphate in thepharmaceutical formulation is about 50 mg/mL, about 51 mg/mL, about 52mg/mL, about 53 mg/mL, about 54 mg/mL, about 55 mg/mL, about 56 mg/mL,about 57 mg/mL, about 58 mg/mL, about 59 mg/mL, about 60 mg/mL, about 61mg/mL, about 62 mg/mL, about 63 mg/mL, about 64 mg/mL, about 65 mg/mL,about 66 mg/mL, about 67 mg/mL, about 68 mg/mL, about 69 mg/mL, or about70 mg/mL. In some embodiments, the one or more inactive ingredients areselected from a buffer agent, a chelating agent, an antioxidant, a pHadjustor, and a solvent. In some embodiments, the buffer agent isselected from monobasic sodium phosphate anhydrous and dibasic sodiumphosphate anhydrous. In some embodiments, the chelating agent isdisodium EDTA. In some embodiments, the antioxidant is monothioglycerol.In some embodiments, the pH adjustor is selected from sodium hydroxideand HCl. In some embodiments, the solvent is water.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofembodiments of the invention, will be better understood when read inconjunction with the appended drawings and figures.

FIG. 1 illustrates the stability of three lead formulations.

FIG. 2 illustrates a typical chromatogram of HCP using the developedanalytical method described herein.

FIG. 3A illustrates the acid hydrolysis of HCP using 0.1 N HCl. FIG. 3Billustrates alkali hydrolysis of HCP using 0.1 N NaOH. FIG. 3Cillustrates the thermal degradation of HCP using dry heat.

FIG. 4 illustrates the stability of two formulations (#3 and #7) over 6months.

FIG. 5 illustrates the stability of two formulations (#3 and #10) over 6months.

FIG. 6 is a perspective view of an injector in accordance with anexemplary embodiment of the present invention.

FIG. 7 is a sectional view of the injector of FIG. 6.

FIG. 8 is a sectional view of the injector of FIG. 6 with the needleguard in a retracted position.

FIG. 9 is a sectional view of the injector of FIG. 6 with the medicamentcontainer in an injection position.

FIG. 10 is a sectional view of the injector of FIG. 6 after medicamenthas been injected.

FIG. 11 is a sectional view of the injector of FIG. 6 after an injectionwith the needle guard in an extended position.

While the above-identified drawings set forth presently disclosedembodiments, other embodiments are also contemplated, as noted in thediscussion. This disclosure presents illustrative embodiments by way ofrepresentation and not limitation. Numerous other modifications andembodiments can be devised by those skilled in the art which fall withinthe scope and spirit of the principles of the presently disclosedembodiments.

DETAILED DESCRIPTION

The present invention is directed to pharmaceutical formulationsincluding hydrocortisone, one or more hydrocortisone prodrugs, e.g.,hydrocortisone esters, and/or any salts thereof, including, withoutlimitation, stable liquid formulations using hydrocortisone sodiumphosphate as the active ingredient.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entireties.

As used herein, the terms “administer,” “administration,” or“administering” refer to (1) providing, giving, dosing, and/orprescribing by either a health practitioner or his authorized agent orunder his or her direction according to the disclosure, and/or (2)putting into, taking, or consuming by a subject, for example a mammal,including a human, according to the disclosure.

The terms “co-administration,” “co-administering,” “administered incombination with,” “administering in combination with,” “simultaneous,”and “concurrent,” as used herein, encompass administration of two ormore active pharmaceutical ingredients to a subject so that both activepharmaceutical ingredients and/or their metabolites are present in thesubject at the same time. Co-administration includes simultaneousadministration in separate compositions, administration at differenttimes in separate compositions, or administration in a composition inwhich two or more active pharmaceutical ingredients are present. In someembodiments, simultaneous administration in separate compositions andadministration in a composition in which both agents are present arepreferred.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or combination of compounds as describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment. A therapeutically effectiveamount may vary depending upon the intended application (in vitro or invivo), or the subject and disease condition being treated (e.g., theweight, age and gender of the subject), the severity of the diseasecondition, the manner of administration, etc., which can readily bedetermined by one of ordinary skill in the art. The term also applies toa dose that will induce a particular response in target cells (e.g., thereduction of platelet adhesion and/or cell migration). The specific dosewill vary depending on the subject to whom the dose is to beadministered, the particular compounds chosen, the dosing regimen to befollowed, whether the compound is administered in combination with othercompounds, timing of administration, the tissue to which it isadministered, and the physical delivery system in which the compound iscarried.

A “therapeutic effect” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit. A prophylactic effectincludes delaying or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, or any combination thereof.

As used herein, the terms “treat,” “treatment,” and/or “treating” mayrefer to the management of a disease, disorder, or pathologicalcondition, or symptom thereof with the intent to cure, ameliorate,stabilize, and/or control the disease, disorder, pathological conditionor symptom thereof. Regarding control of the disease, disorder, orpathological condition more specifically, “control” may include theabsence of condition progression, as assessed by the response to themethods recited herein, where such response may be complete (e.g.,placing the disease in remission) or partial (e.g., lessening orameliorating any symptoms associated with the condition). As usedherein, the terms “prevent,” “preventing,” and/or “prevention” may referto reducing the risk of developing a disease, disorder, or pathologicalcondition.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Preferred inorganic acids from whichsalts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.Preferred organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, phosphoric acid, succinic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptablebase addition salts can be formed with inorganic and organic bases.Inorganic bases from which salts can be derived include, for example,sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese and aluminum. Organic bases from which salts can bederived include, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins. Specific examples includeisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts. The term “cocrystal”refers to a molecular complex derived from a number of cocrystal formersknown in the art. Unlike a salt, a cocrystal typically does not involvehydrogen transfer between the cocrystal and the drug, and insteadinvolves intermolecular interactions, such as hydrogen bonding, aromaticring stacking, or dispersive forces, between the cocrystal former andthe drug in the crystal structure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” or “physiologically compatible” carrier or carrier medium isintended to include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and inert ingredients. The use of such pharmaceuticallyacceptable carriers or pharmaceutically acceptable excipients for activepharmaceutical ingredients is well known in the art. Except insofar asany conventional pharmaceutically acceptable carrier or pharmaceuticallyacceptable excipient is incompatible with the active pharmaceuticalingredient, its use in the therapeutic compositions of the invention iscontemplated. Additional active pharmaceutical ingredients, such asother drugs, can also be incorporated into the described compositionsand methods.

A “prodrug” refers to a derivative of a compound described herein, thepharmacologic action of which results from the conversion by chemical ormetabolic processes in vivo to the active compound. Prodrugs include,without limitation, compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxyl or carboxylic acid group of hydrocortisone. The aminoacid residues include but are not limited to the 20 naturally occurringamino acids commonly designated by one or three letter symbols but alsoinclude, for example, 4-hydroxyproline, hydroxylysine, desmosine,isodesmosine, 3-methylhistidine, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters (e.g.,methyl esters and acetoxy methyl esters). Prodrug esters as employedherein includes esters and carbonates formed by reacting one or morehydroxyls of compounds of the method of the invention with alkyl,alkoxy, or aryl substituted acylating agents employing procedures knownto those skilled in the art to generate acetates, phosphates,succinates, butyrates, pivalates, methylcarbonates, benzoates and thelike. As further examples, free hydroxyl groups may be derivatized usinggroups including but not limited to hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs ofhydroxyl and amino groups are also included, as are carbonate prodrugs,sulfonate prodrugs, sulfonate esters and sulfate esters of hydroxylgroups. Free amines can also be derivatized to amides, sulfonamides orphosphonamides. All of the stated prodrug moieties may incorporategroups including but not limited to ether, amine and carboxylic acidfunctionalities. Moreover, any compound that can be converted in vivo toprovide the bioactive agent (e.g., hydrocortisone) is a prodrug withinthe scope of the invention. Various forms of prodrugs are well known inthe art. A comprehensive description of prodrugs and prodrug derivativesare described in: (a) The Practice of Medicinal Chemistry, Camille G.Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, editedby H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design andDevelopment, P. Krogsgaard-Larson and H. Bundgaard, eds., (HarwoodAcademic Publishers, 1991). In general, prodrugs may be designed toimprove the penetration of a drug across biological membranes in orderto obtain improved drug absorption, to prolong duration of action of adrug (slow release of the parent drug from a prodrug, decreasedfirst-pass metabolism of the drug), to target the drug action (e.g.,organ or tumor-targeting, lymphocyte targeting), to modify or improveaqueous solubility of a drug (e.g., i.v. preparations and eyedrops), toimprove topical drug delivery (e.g., dermal and ocular drug delivery),to improve the chemical/enzymatic stability of a drug, or to decreaseoff-target drug effects, and more generally in order to improve thetherapeutic efficacy of the compounds utilized in the invention.

Unless otherwise stated, the chemical structures depicted herein areintended to include compounds which differ only in the presence of oneor more isotopically enriched atoms. For example, compounds where one ormore hydrogen atoms is replaced by deuterium or tritium, or wherein oneor more carbon atoms is replaced by ¹³C-enriched or ¹⁴C-enrichedcarbons, are within the scope of this invention.

When ranges are used herein to describe, for example, physical orchemical properties such as molecular weight or chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. Use of the term “about” whenreferring to a number or a numerical range means that the number ornumerical range referred to is an approximation within experimentalvariability (or within statistical experimental error), and thus thenumber or numerical range may vary. The variation is typically from 0%to 15%, from 0% to 10%, from 0% to 5%, or the like, of the stated numberor numerical range.

As used herein, the term “about” means that amounts, sizes,formulations, parameters, shapes and other quantities andcharacteristics are not, and need not be exact, but may be approximateand/or larger or smaller, as desired, reflecting tolerances, conversionfactors, rounding off, measurement error and the like, and other factorsknown to those of skill in the art. In general, an amount, size,formulation, parameter, shape or other quantity or characteristic is“about” or “approximate” whether or not expressly stated to be such. Theterm “about” generally refers to a particular numeric value that iswithin an acceptable error range as determined by one of ordinary skillin the art, which will depend in part on how the numeric value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean a range of ±20%, ±10%, or ±5% of a givennumeric value.

The transitional terms “comprising”, “consisting essentially of” and“consisting of”, when used in the appended claims, in original andamended form, define the claim scope with respect to what unrecitedadditional claim elements or steps, if any, are excluded from the scopeof the claim(s). The term “comprising” is intended to be inclusive oropen-ended and does not exclude any additional, unrecited element,method, step or material. The term “consisting of” excludes any element,step or material other than those specified in the claim and, in thelatter instance, impurities ordinarily associated with the specifiedmaterial(s). The term “consisting essentially of” limits the scope of aclaim to the specified elements, steps or material(s) and those that donot materially affect the basic and novel characteristic(s) of theclaimed invention. All compounds, compositions, formulations, andmethods described herein that embody the present invention can, inalternate embodiments, be more specifically defined by any of thetransitional terms “comprising,” “consisting essentially of” and“consisting of” The term “comprising” (and related terms such as“comprise” or “comprises” or “having” or “including”) includes thoseembodiments such as, for example, an embodiment of any composition ofmatter, method, or process that “consist of” or “consist essentially of”the described features.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., (C₁₋₁₀)alkyl orC₁₋₁₀ alkyl). Whenever it appears herein, a numerical range such as “1to 10” refers to each integer in the given range, e.g., “1 to 10 carbonatoms” means that the alkyl group may consist of 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms,although the definition is also intended to cover the occurrence of theterm “alkyl” where no numerical range is specifically designated.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl,tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl,nonyl and decyl. The alkyl moiety may be attached to the rest of themolecule by a single bond, such as for example, methyl (Me), ethyl (Et),n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl) and 3-methylhexyl. Unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted by one or more of substituents which are independentlyheteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —SR^(a),—S(O)_(t)R^(a)-(where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.The alkyl moiety, whether saturated or unsaturated, may be branched,straight chain, or cyclic.

An “alkene” or “alkenyl” moiety refers to a group consisting of at leasttwo carbon atoms and at least one carbon-carbon double bond, and an“alkyne” moiety refers to a group consisting of at least two carbonatoms and at least one carbon-carbon triple bond.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,(C₂₋₁₀)alkenyl or C₂₋₁₀ alkenyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the givenrange—e.g., “2 to 10 carbon atoms” means that the alkenyl group mayconsist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10carbon atoms. The alkenyl moiety may be attached to the rest of themolecule by a single bond, such as for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl.Unless stated otherwise specifically in the specification, an alkenylgroup is optionally substituted by one or more substituents which areindependently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —SR^(a),—S(O)_(t)R^(a)-(where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl-cycloalkyl” refers to an -(alkenyl)cycloalkyl radical wherealkenyl and cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkenyl and cycloalkyl respectively.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that containsonly carbon and hydrogen, and may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms (i.e., (C₃₋₁₀)cycloalkyl or C₃₋₁₀ cycloalkyl). Whenever it appearsherein, a numerical range such as “3 to 10” refers to each integer inthe given range—e.g., “3 to 10 carbon atoms” means that the cycloalkylgroup may consist of 3 carbon atoms, etc., up to and including 10 carbonatoms. Illustrative examples of cycloalkyl groups include, but are notlimited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwisespecifically in the specification, a cycloalkyl group is optionallysubstituted by one or more substituents which independently are: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido,heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —S(O)_(t)R^(a)-(where t is 1 or 2),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Cycloalkyl-alkenyl” refers to a -(cycloalkyl)alkenyl radical wherecycloalkyl and alkenyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkenyl, respectively.

“Acyl” refers to the groups (alkyl)-C(O)—, (aryl)-C(O)—,(heteroaryl)-C(O)—, (heteroalkyl)-C(O)— and (heterocycloalkyl)-C(O)—,wherein the group is attached to the parent structure through thecarbonyl functionality. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise specifically inthe specification, the alkyl, aryl or heteroaryl moiety of the acylgroup is optionally substituted by one or more substituents which areindependently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Ester” refers to, without limitation, a chemical radical of formula—COOR, where R is selected from the group consisting of alkyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon). The procedures andspecific groups to make esters are known to those of skill in the artand can readily be found in seminal sources such as Greene and Wuts,Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons,New York, N.Y., 1999, which is incorporated herein by reference in itsentirety. Unless stated otherwise specifically in the specification, anester group is optionally substituted by one or more substituents whichindependently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Ester” also refers to, without limitation, a phosphate.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical may be optionally substituted as defined above foran alkyl group.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space—i.e., having a different stereochemical configuration.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate. “Diastereoisomers” are stereoisomers that have atleast two asymmetric atoms, but which are not mirror-images of eachother. The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon can be specified by either (R) or(S). Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds described herein containone or more asymmetric centers and can thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that can be defined, interms of absolute stereochemistry, as (R) or (S). The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible isomers, including racemic mixtures, optically pureforms and intermediate mixtures. Optically active (R)- and (S)-isomerscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. “Tautomerization” is a form of isomerization andincludes prototropic or proton-shift tautomerization, which isconsidered a subset of acid-base chemistry. “Prototropictautomerization” or “proton-shift tautomerization” involves themigration of a proton accompanied by changes in bond order, often theinterchange of a single bond with an adjacent double bond. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. An example of tautomerization is keto-enoltautomerization. A specific example of keto-enol tautomerization is theinterconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-onetautomers. Another example of tautomerization is phenol-ketotautomerization. A specific example of phenol-keto tautomerization isthe interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

“Substituted” means that the referenced group may have attached one ormore additional groups, radicals or moieties individually andindependently selected from, for example, acyl, alkyl, alkylaryl,cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl,heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl,isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl,perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl,sulfoxyl, sulfonate, urea, and amino, including mono- and di-substitutedamino groups, and protected derivatives thereof. The substituentsthemselves may be substituted, for example, a cycloalkyl substituent mayitself have a halide substituent at one or more of its ring carbons. Theterm “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

DETAILED DESCRIPTION Formulations

In one embodiment, the invention relates to a pharmaceutical formulationincluding hydrocortisone, one or more hydrocortisone prodrugs, e.g., ahydrocortisone ester, and/or any salts thereof.

Hydrocortisone is the name for the hormone cortisol when supplied as amedication. It is used in oral administration, intravenous injection, ortopical application. It is used as an immunosuppressive drug, given byinjection in the treatment of severe allergic reactions such asanaphylaxis and angioedema. It may be used topically for allergicrashes, eczema, psoriasis, itching and other inflammatory skinconditions.

Therapeutic hydrocortisone is a synthetic or semisynthetic analog ofnatural hydrocortisone hormone produced by the adrenal glands withprimary glucocorticoid and minor mineralocorticoid effects. As aglucocorticoid receptor agonist, hydrocortisone promotes proteincatabolism, gluconeogenesis, capillary wall stability, renal excretionof calcium, and suppresses immune and inflammatory responses.

The empirical formula of Hydrocortisone is C₂₁H₃₀O₅. The molecularweight is 362.46 g/mol. The structural formula is:

Hydrocortisone

Hydrocortisone is available as a crystalline, white powder and hasbitter taste. Its melting point is 220° C. It is a water insoluble witha reported solubility of about 0.32 mg/mL in water. Reported solubilityin propylene glycol is 12.7 mg/mL. The octanol/water partitioncoefficient value of hydrocortisone is 1.61. It is sensitive to lightand unstable in strong acids and alkalies.

Hydrocortisone sodium phosphate is an organic salt. Its molecularformula is C₂₁H₂₉Na₂O₈P and its molecular weight is 486.4 g/mol, and ithas the following structure:

Hydrocortisone Sodium Phosphate

Any antioxidant suitable for parenteral administration can be used inthe formulations of the invention. In some embodiments, the antioxidantis one or more of butylated hydroxy toluene (BHT), tocopherol, butylatedhydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid and saltsthereof, vitamin E, niacinamide, methionine, monothioglycerol, sodiumbisulfate, cysteine, dithionite sodium, gentisic acid, and/or glutamatemonosodium.

Pharmaceutical Compositions

In some embodiments, the concentration of the hydrocortisone,hydrocortisone prodrug, i.e., hydrocortisone ester, or pharmaceuticallyacceptable salts of thereof, described herein is less than, or no morethan, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%,18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%,2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of thepharmaceutical formulations described herein.

In some embodiments, the concentration of the hydrocortisone,hydrocortisone prodrug, i.e., hydrocortisone ester, or pharmaceuticallyacceptable salts of thereof, described herein is greater than 90%, 80%,70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%,18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%,13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25%11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%,8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%,5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%,2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%,0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%,0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%,0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001%w/w, w/v, or v/v of the pharmaceutical formulations described herein.

In some embodiments, the concentration of the hydrocortisone,hydrocortisone prodrug, i.e., hydrocortisone ester, or pharmaceuticallyacceptable salts of thereof, described herein is in the range from about0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% toabout 27%, about 0.05% to about 26%, about 0.06% to about 25%, about0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%,about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% toabout 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9%to about 12% or about 1% to about 10% w/w, w/v, or v/v of thepharmaceutical formulations described herein.

In some embodiments, the concentration of the hydrocortisone,hydrocortisone prodrug, i.e., hydrocortisone ester, or pharmaceuticallyacceptable salts of thereof, described herein is in the range from about0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%,about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% toabout 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v,or v/v of the pharmaceutical formulations described herein.

In some embodiments, the amount of each of the active and/or inactivepharmaceutical ingredients provided in the pharmaceutical compositionsof the invention, such as a hydrocortisone, hydrocortisone prodrug,i.e., hydrocortisone ester, or pharmaceutically acceptable salts ofthereof, and/or an antioxidant, is equal to or less than, or no morethan 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g,0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g,0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g,0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g,0.0002 g, or 0.0001 g in a pharmaceutical formulation described herein.

In some embodiments, the amount of each of the active and/or inactivepharmaceutical ingredients provided in the pharmaceutical compositionsof the invention, such as a hydrocortisone, hydrocortisone prodrug,i.e., hydrocortisone ester, or pharmaceutically acceptable salts ofthereof, and/or an antioxidant, is more than 0.0001 g, 0.0002 g, 0.0003g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g,0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g,0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g,0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g,0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g,5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g in apharmaceutical formulation described herein.

Each of the active pharmaceutical ingredients according to the inventionis effective over a wide dosage range. For example, in the treatment ofadult humans, dosages independently range from 0.01 to 1000 mg, from 0.5to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day areexamples of dosages that may be used. Effective dosages from 50 to 200mg per week are also examples of dosages that may be used. In oneembodiment, the effective weekly dosage is about 50 mg. In oneembodiment, the effective weekly dosage is about 100 mg. In oneembodiment, the effective weekly dosage is about 150 mg. In oneembodiment, the effective weekly dosage is about 200 mg. In oneembodiment, the effective weekly dosage is about 250 mg.

The exact dosage will depend upon the route of administration, the formin which the compound is administered, the gender and age of the subjectto be treated, the body weight of the subject to be treated, and thepreference and experience of the attending physician. Theclinically-established dosages of hydrocortisone, hydrocortisoneprodrug, i.e., hydrocortisone ester, or pharmaceutically acceptablesalts of thereof, for example hydrocortisone phosphate, may also be usedif appropriate.

In some embodiments, the concentration of hydrocortisone sodiumphosphate ranges from 50 mg/mL to 200 mg/mL. In some embodiments, theconcentration of BHT ranges from 0.01% to 0.1%. In some embodiments, theconcentration of monothioglycerol ranges from 0.1 mg/mL to 10 mg/mL.

Pharmaceutical Compositions for Injection

In some embodiments, a pharmaceutical composition is provided forinjection containing an active pharmaceutical ingredient or combinationof active pharmaceutical ingredients, such as a hydrocortisone ester,for example hydrocortisone sodium phosphate, and a pharmaceuticalexcipient suitable for injection.

The forms in which the compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (andsuitable mixtures thereof), cyclodextrin derivatives, and vegetable oilsmay also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, for the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal preservatives orpreservative agents, for example, parabens, chlorobutanol, phenol,sorbic acid, and thimerosal.

Sterile injectable solutions are prepared by incorporating an activepharmaceutical ingredient or combination of active pharmaceuticalingredients in the required amounts in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certaindesirable methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Administration of an active pharmaceutical ingredient or combination ofactive pharmaceutical ingredients or a pharmaceutical compositionthereof can be effected by any method that enables delivery of thecompounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intradermal, intravascular,intraperitoneal or infusion), topical (e.g., transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. The active pharmaceutical ingredient or combinationof active pharmaceutical ingredients can also be administeredintraadiposally or intrathecally.

An injector may be used to inject the pharmaceutical formulationdescribed herein. The formulation may be injected subcutaneously orintramuscularly. In some embodiments, the injector is a single usedevice that is discarded or recycled after administering a single dose.In other embodiments, the injector is a multi-dose injector. Someinjectors that are contemplated for use with the formulation describedherein are disclosed in U.S. Pat. Nos. 8,021,335; 8,814,834; 8,945,063;and 10,300,207, all incorporated herein by reference.

Referring to FIGS. 5-11, there is shown an injector, generallydesignated 30, in accordance with an exemplary embodiment of the presentinvention. Injector 30 may be an auto-injector. Injector 30 may includea housing 32. An end cap 34 may be coupled to housing 30. Injector 30may include a needle 74 fluidly coupled to a formulation container 72(e.g., syringe). A plunger 70 may be movable relative to formulationcontainer 72 to force formulation out of needle 74 during an injection.A ram 58 may be operatively associated with plunger 70 such that axialmovement of ram 58 causes movement of plunger 70. An energy source 66(e.g., biasing element, spring) may move plunger 70 when injector 30 istriggered.

A needle guard 78 may be movably coupled to housing 32. Needle guard 78may be moveable between an extended position (FIG. 7) and a retractedposition (FIG. 8). Needle guard 78 may be movable when a distal end ofneedle guard 78 is pressed against an injection site. Movement of needleguard 78 relative to housing 32 may trigger injector 30 to start aninjection sequence.

Formulation container 72 may be movable relative to housing 32 between astorage position (FIG. 7) and an injection position (FIG. 9).Formulation container 72 may be moved to the injection position afterneedle guard 78 triggers injector 30. A second energy source 56 (e.g.,biasing element or spring) may move formulation container 72 from thestorage position to the injection position. Energy source 66 may moveram 58 once formulation container 72 is in the injection position todispense the formulation through needle 74. Needle guard 78 may returnto the extended position (FIG. 11) once the formulation has beendispensed.

Kits

The invention also provides kits. The kits include an activepharmaceutical ingredient or combination of active pharmaceuticalingredients, either alone or in combination in suitable packaging, andwritten material that can include instructions for use, discussion ofclinical studies and listing of side effects. Such kits may also includeinformation, such as scientific literature references, package insertmaterials, clinical trial results, and/or summaries of these and thelike, which indicate or establish the activities and/or advantages ofthe composition, and/or which describe dosing, administration, sideeffects, drug interactions, or other information useful to the healthcare provider. Such information may be based on the results of variousstudies, for example, studies using experimental animals involving invivo models and studies based on human clinical trials. The kit mayfurther contain another active pharmaceutical ingredient. In selectedembodiments, an active pharmaceutical ingredient or combination ofactive pharmaceutical ingredients are provided as separate compositionsin separate containers within the kit. In selected embodiments, anactive pharmaceutical ingredient or combination of active pharmaceuticalingredients are provided as a single composition within a container inthe kit. Suitable packaging and additional articles for use (e.g.,measuring cup for liquid preparations, foil wrapping to minimizeexposure to air, and the like) are known in the art and may be includedin the kit. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits may also, in selectedembodiments, be marketed directly to the consumer.

In some embodiments, the invention provides a kit including acomposition including a therapeutically effective amount of an activepharmaceutical ingredient (e.g., a hydrocortisone sodium phosphate) orcombination of active pharmaceutical ingredients or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Thesecompositions are typically pharmaceutical compositions. The kit is forco-administration of the active pharmaceutical ingredient or combinationof active pharmaceutical ingredients, either simultaneously orseparately.

In some embodiments, the invention provides for a kit including acomposition including a therapeutically effective amount ofhydrocortisone sodium phosphate alone or in combination with activepharmaceutical ingredients or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug in an oil combined with anantioxidant in a prefilled syringe (PFS) or vial. In some embodiments,the prefilled syringe or the vial are transparent. The kit includessuitable packaging for protecting the prefilled syringe or vial fromlight. In some embodiments this includes an autoinjector. In otherembodiments, this includes an autoinjector with a viewing window toallow inspection of the drug prior to injection. In yet otherembodiments, the autoinjector is in a carton to prevent light access tothe drug.

The prefilled syringe or the vial may include one dose or multipledoses. In some embodiments, a prefilled syringe or vial includingmultiple doses is bigger, i.e., has a larger volume than a prefilledsyringe or vial including only one dose. In some embodiments, thesurface area to the volume ratio of a prefilled syringe or vial getssmaller as the prefilled syringe or vial gets larger in volume.

Such kits may include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider and/or the patient. Suchinformation may instruct the user to keep the prefilled syringe orprefilled syringe and autoinjector in a carton to protect thepharmaceutical ingredients from light.

In some embodiments, the invention provides a kit including (1) acomposition including a therapeutically effective amount of an activepharmaceutical ingredient (e.g., a hydrocortisone sodium phosphate) orcombination of active pharmaceutical ingredients or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and(2) a diagnostic test for determining whether a patient is in need ofhydrocortisone sodium phosphate administration.

Dosages and Dosing Regimens

The amounts of the pharmaceutical compositions administered using themethods herein, such as the dosages of hydrocortisone sodium phosphate,will be dependent on the subject, e.g., human or mammal being treated,the severity of the disorder or condition, the rate of administration,the disposition of the active pharmaceutical ingredients and thediscretion of the prescribing physician. Dosage in the range of 50 to100 mg per week for administration to a human may be adequate to achievean effective therapeutic level. At times, dosages of 50 to 100 mg perweek over several weeks may be required to achieve the desiredtherapeutic level. However, an effective dosage is in the range of about0.001 to about 100 mg per kg body weight per day, such as about 1 toabout 35 mg/kg/day, in single or divided doses. For a 70 kg human, thiswould amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5g/day. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful sideeffect—e.g., by dividing such larger doses into several small doses foradministration throughout the day. The dosage of the pharmaceuticalcompositions and active pharmaceutical ingredients may be provided inunits of mg/kg of body mass or in mg/m² of body surface area.

In some embodiments, a pharmaceutical composition or activepharmaceutical ingredient is administered in multiple doses. In anembodiment, a pharmaceutical composition is administered in multipledoses. Dosing may be once, twice, three times, four times, five times,six times, or more than six times per day. Dosing may be once a month,once every two weeks, once a week, or once every other day. In otherembodiments, a pharmaceutical composition is administered about once perday to about 6 times per day. In some embodiments, a pharmaceuticalcomposition is administered once daily, while in other embodiments, apharmaceutical composition is administered twice daily, and in otherembodiments a pharmaceutical composition is administered three timesdaily.

Administration of the active pharmaceutical ingredients may continue aslong as necessary. In selected embodiments, a pharmaceutical compositionis administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 day(s).Other embodiments require the pharmaceutical composition is administeredfor more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 week(s). In someembodiments, a pharmaceutical composition is administered for less than,or no more than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day(s). In someembodiments, a pharmaceutical composition is administered chronically onan ongoing basis—e.g., for the treatment of chronic effects. In someembodiments, the administration of a pharmaceutical compositioncontinues for less than, or no more than about 7 days. In yet anotherembodiment the administration continues for more than about 6, 10, 14,28 days, two months, six months, or one year. In some cases, continuousdosing is achieved and maintained as long as necessary.

In some embodiments, an effective dosage of an active pharmaceuticalingredient disclosed herein is in the range of about 1 mg to about 500mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25mg to about 200 mg, about 50 mg to 200 mg, about 10 mg to about 200 mg,about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg toabout 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg,about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 50 mg toabout 100 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg,about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg toabout 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg,about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mgto about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210mg, about 195 mg to about 205 mg, or about 198 to about 202 mg. In someembodiments, an effective dosage of an active pharmaceutical ingredientdisclosed herein is less than, or no more than about 25 mg, less than,or no more than about 50 mg, less than, or no more than about 75 mg,less than, or no more than about 100 mg, less than, or no more thanabout 125 mg, less than, or no more than about 150 mg, less than, or nomore than about 175 mg, less than, or no more than about 200 mg, lessthan, or no more than about 225 mg, or less than, or no more than about250 mg. In some embodiments, an effective dosage of an activepharmaceutical ingredient disclosed herein is greater than about 25 mg,greater than about 50 mg, greater than about 75 mg, greater than about100 mg, greater than about 125 mg, greater than about 150 mg, greaterthan about 175 mg, greater than about 200 mg, greater than about 225 mg,or greater than about 250 mg.

In some embodiments, an effective dosage of an active pharmaceuticalingredient disclosed herein is in the range of about 0.01 mg/kg to about200 mg/kg, or about 0.1 to 100 mg/kg, or about 1 to 50 mg/kg. In someembodiments, an active pharmaceutical ingredient is administered at adosage of 10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, 150, or200 mg BID. In some embodiments, an active pharmaceutical ingredient isadministered at a dosage of 10 to 500 mg BID, including 1, 5, 10, 15,25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID.

In some instances, dosage levels below the lower limit of the aforesaidranges may be more than adequate, while in other cases still largerdoses may be employed without causing any harmful side effect, e.g., bydividing such larger doses into several small doses for administrationthroughout the day. As those skilled in the art will appreciate, thedosage actually administered will depend upon the condition beingtreated, the age, health and weight of the recipient, the type ofconcurrent treatment, if any, and the frequency of treatment. Moreover,the effective dosage amount may be determined by one skilled in the arton the basis of routine empirical activity testing to measure thebioactivity of the compound(s) in a bioassay, and thus establish theappropriate dosage to be administered.

An effective amount of the combination of the active pharmaceuticalingredient may be administered in either single or multiple doses by anyof the accepted modes of administration of agents having similarutilities, including rectal, buccal, intranasal and transdermal routes,by intra-arterial injection, intravenously, intraperitoneally,parenterally, intramuscularly, subcutaneously, intradermally, orally,topically, or as an inhalant.

In some embodiments, the compositions described herein further includecontrolled-release, sustained release, or extended-release therapeuticdosage forms for administration of the compounds described herein, whichinvolves incorporation of the compounds into a suitable delivery systemin the formation of certain compositions. This dosage form controlsrelease of the compound(s) in such a manner that an effectiveconcentration of the compound(s) in the bloodstream may be maintainedover an extended period of time, with the concentration in the bloodremaining relatively constant, to improve therapeutic results and/orminimize side effects. Additionally, a controlled-release system wouldprovide minimum peak to trough fluctuations in blood plasma levels ofthe compound.

The following clauses describe certain embodiments.

Clause 1. A pharmaceutical formulation comprising hydrocortisone, ahydrocortisone prodrug, and/or a pharmaceutically acceptable salt of anyone thereof, and one or more inactive ingredients.

Clause 2. The pharmaceutical formulation of clause 1, wherein thehydrocortisone prodrug is a hydrocortisone ester.

Clause 3. The pharmaceutical formulation of clause 1 or 2, wherein thehydrocortisone prodrug or pharmaceutically acceptable salt thereof isselected from hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, hydrocortisone hydrogen succinate, hydrocortisone butyrate,hydrocortisone acetate.

Clause 4. The pharmaceutical formulation of clause 1 or 2, wherein thehydrocortisone prodrug or pharmaceutically acceptable salt thereof ishydrocortisone sodium phosphate.

Clause 5. The pharmaceutical formulation of clause 4, wherein theconcentration of hydrocortisone sodium phosphate in the pharmaceuticalformulation is between about 5 mg/mL and about 100 mg/mL.

Clause 6. The pharmaceutical formulation of clause 4, wherein theconcentration of hydrocortisone sodium phosphate in the pharmaceuticalformulation is between about 50 mg/mL and about 100 mg/mL.

Clause 7. The pharmaceutical formulation of clause 4, wherein theconcentration of hydrocortisone sodium phosphate in the pharmaceuticalformulation is between about 25 mg/mL and about 75 mg/mL.

Clause 8. The pharmaceutical formulation of clause 4, wherein theconcentration of hydrocortisone sodium phosphate in the pharmaceuticalformulation is about 50 mg/mL, about 51 mg/mL, about 52 mg/mL, about 53mg/mL, about 54 mg/mL, about 55 mg/mL, about 56 mg/mL, about 57 mg/mL,about 58 mg/mL, about 59 mg/mL, about 60 mg/mL, about 61 mg/mL, about 62mg/mL, about 63 mg/mL, about 64 mg/mL, about 65 mg/mL, about 66 mg/mL,about 67 mg/mL, about 68 mg/mL, about 69 mg/mL, or about 70 mg/mL.

Clause 9. The pharmaceutical formulation of any one of clauses 1 to 8,wherein the one or more inactive ingredients are selected from a bufferagent, a chelating agent, an antioxidant, a pH adjustor, and a solvent.

Clause 10. The pharmaceutical formulation of clause 9, wherein thebuffer agent is selected from monobasic sodium phosphate anhydrous anddibasic sodium phosphate anhydrous.

Clause 11. The pharmaceutical formulation of clause 9, wherein thechelating agent is disodium EDTA.

Clause 12. The pharmaceutical formulation of clause 9, wherein theantioxidant is monothioglycerol.

Clause 13. The pharmaceutical formulation of clause 9, wherein the pHadjustor is selected from sodium hydroxide and HCl.

Clause 14. The pharmaceutical formulation of clause 9, wherein thesolvent is water.

Clause 101. An aqueous pharmaceutical formulation comprising from about50 to about 150 mg/mL hydrocortisone sodium phosphate, from about 2.5 toabout 12.5 mg/mL monothioglycerol, and water.

Clause 102. An aqueous pharmaceutical formulation comprising from about60 to about 135 mg/mL hydrocortisone sodium phosphate, from about 5 toabout 10 mg/mL monothioglycerol, and water.

Clause 201. The aqueous pharmaceutical formulation of clause 101 or 102,comprising from about 50 to about 60 mg/mL hydrocortisone sodiumphosphate, from about 60 to about 70 mg/mL hydrocortisone sodiumphosphate, or from about 70 to about 80 mg/mL hydrocortisone sodiumphosphate.

Clause 301. The aqueous pharmaceutical formulation of clause 101 or 102,comprising from about 60 to about 65 mg/mL hydrocortisone sodiumphosphate, or from about 65 to about 70 mg/mL hydrocortisone sodiumphosphate.

Clause 401. The aqueous pharmaceutical formulation of clauses 101 or102, comprising from about 120 to about 130 mg/mL hydrocortisone sodiumphosphate, from about 130 to about 140 mg/mL hydrocortisone sodiumphosphate, or from about 140 to about 150 mg/mL hydrocortisone sodiumphosphate.

Clause 501. The aqueous pharmaceutical formulation of clauses 101 or102, comprising from about 130 to about 135 mg/mL hydrocortisone sodiumphosphate, or from about 135 to about 140 mg/mL hydrocortisone sodiumphosphate.

Clause 601. The aqueous pharmaceutical formulation of clauses 101 or102, comprising about 50 mg/mL hydrocortisone sodium phosphate, about 55mg/mL hydrocortisone sodium phosphate, about 60 mg/mL hydrocortisonesodium phosphate, about 65 mg/mL hydrocortisone sodium phosphate, about70 mg/mL hydrocortisone sodium phosphate, about 75 mg/mL hydrocortisonesodium phosphate, about 80 mg/mL hydrocortisone sodium phosphate, about85 mg/mL hydrocortisone sodium phosphate, about 90 mg/mL hydrocortisonesodium phosphate, about 95 mg/mL hydrocortisone sodium phosphate, about100 mg/mL hydrocortisone sodium phosphate, about 105 mg/mLhydrocortisone sodium phosphate, about 110 mg/mL hydrocortisone sodiumphosphate, about 115 mg/mL hydrocortisone sodium phosphate, about 120mg/mL hydrocortisone sodium phosphate, about 125 mg/mL hydrocortisonesodium phosphate, about 130 mg/mL hydrocortisone sodium phosphate, about135 mg/mL hydrocortisone sodium phosphate, about 140 mg/mLhydrocortisone sodium phosphate, about 145 mg/mL hydrocortisone sodiumphosphate, or about 150 mg/mL hydrocortisone sodium phosphate.

Clause 701. An aqueous pharmaceutical formulation comprising about 60mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 702. An aqueous pharmaceutical formulation comprising about 61mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 703. An aqueous pharmaceutical formulation comprising about 62mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 704. An aqueous pharmaceutical formulation comprising about 63mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 705. An aqueous pharmaceutical formulation comprising about 64mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 706. An aqueous pharmaceutical formulation comprising about 65mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 707. An aqueous pharmaceutical formulation comprising about 66mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 708. An aqueous pharmaceutical formulation comprising about 67mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 709. An aqueous pharmaceutical formulation comprising about 68mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 710. An aqueous pharmaceutical formulation comprising about 69mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 711. An aqueous pharmaceutical formulation comprising about 70mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 801. An aqueous pharmaceutical formulation comprising about 67mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 802. An aqueous pharmaceutical formulation comprising about 67.1mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 803. An aqueous pharmaceutical formulation comprising about 67.2mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 804. An aqueous pharmaceutical formulation comprising about 67.3mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 805. An aqueous pharmaceutical formulation comprising about 67.4mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 806. An aqueous pharmaceutical formulation comprising about 67.5mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 807. An aqueous pharmaceutical formulation comprising about 67.6mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 808. An aqueous pharmaceutical formulation comprising about 67.7mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 809. An aqueous pharmaceutical formulation comprising about 67.8mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 810. An aqueous pharmaceutical formulation comprising about 67.9mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 811. An aqueous pharmaceutical formulation comprising about 68mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 901. An aqueous pharmaceutical formulation comprising about 130mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 902. An aqueous pharmaceutical formulation comprising about 131mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 903. An aqueous pharmaceutical formulation comprising about 132mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 904. An aqueous pharmaceutical formulation comprising about 133mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 905. An aqueous pharmaceutical formulation comprising about 134mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 906. An aqueous pharmaceutical formulation comprising about 135mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 907. An aqueous pharmaceutical formulation comprising about 136mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 908. An aqueous pharmaceutical formulation comprising about 137mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 909. An aqueous pharmaceutical formulation comprising about 138mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 910. An aqueous pharmaceutical formulation comprising about 139mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 911. An aqueous pharmaceutical formulation comprising about 140mg/mL hydrocortisone sodium phosphate, from about 2.5 to about 12.5mg/mL monothioglycerol, and water.

Clause 1001. An aqueous pharmaceutical formulation comprising about 134mg/mL hydrocortisone sodium phosphate, about 134.1 mg/mL hydrocortisonesodium phosphate, about 134.2 mg/mL hydrocortisone sodium phosphate,about 134.3 mg/mL hydrocortisone sodium phosphate, about 134.4 mg/mLhydrocortisone sodium phosphate, about 134.5 mg/mL hydrocortisone sodiumphosphate, about 134.6 mg/mL hydrocortisone sodium phosphate, about134.7 mg/mL hydrocortisone sodium phosphate, about 134.8 mg/mLhydrocortisone sodium phosphate, about 134.9 mg/mL hydrocortisone sodiumphosphate, or about 135 mg/mL hydrocortisone sodium phosphate, fromabout 2.5 to about 12.5 mg/mL monothioglycerol, and water.

Clause 1101. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising from about 2.5 to about 3.5 mg/mLmonothioglycerol, from about 3.5 to about 4.5 mg/mL monothioglycerol,from about 4.5 to about 5.5 mg/mL monothioglycerol, from about 5.5 toabout 6.5 mg/mL monothioglycerol, from about 6.5 to about 7.5 mg/mLmonothioglycerol, from about 7.5 to about 8.5 mg/mL monothioglycerol,from about 8.5 to about 9.5 mg/mL monothioglycerol, from about 9.5 toabout 10.5 mg/mL monothioglycerol, from about 10.5 to about 11.5 mg/mLmonothioglycerol, or from about 11.5 to about 12.5 mg/mLmonothioglycerol.

Clause 1201. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising from about 4 to about 4.25 mg/mLmonothioglycerol, from about 4.25 to about 4.5 mg/mL monothioglycerol,from about 4.5 to about 4.75 mg/mL monothioglycerol, from about 4.75 toabout 5 mg/mL monothioglycerol, from about 5 to about 5.25 mg/mLmonothioglycerol, from about 5.25 to about 5.5 mg/mL monothioglycerol,from about 5.5 to about 5.75 mg/mL monothioglycerol, or from about 5.75to about 6 mg/mL monothioglycerol.

Clause 1301. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising from about 9 to about 9.25 mg/mLmonothioglycerol, from about 9.25 to about 9.5 mg/mL monothioglycerol,from about 9.5 to about 9.75 mg/mL monothioglycerol, from about 9.75 toabout 10 mg/mL monothioglycerol, from about 10 to about 10.25 mg/mLmonothioglycerol, from about 10.25 to about 10.5 mg/mL monothioglycerol,from about 10.5 to about 10.75 mg/mL monothioglycerol, or from about10.75 to about 11 mg/mL monothioglycerol.

Clause 1401. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 4.5 mg/mL monothioglycerol.

Clause 1402. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 4.6 mg/mL monothioglycerol.

Clause 1403. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 4.7 mg/mL monothioglycerol.

Clause 1404. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 4.8 mg/mL monothioglycerol.

Clause 1405. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 4.9 mg/mL monothioglycerol.

Clause 1406. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 5 mg/mL monothioglycerol.

Clause 1407. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 5.1 mg/mL monothioglycerol.

Clause 1408. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 5.2 mg/mL monothioglycerol.

Clause 1409. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 5.3 mg/mL monothioglycerol.

Clause 1410. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 5.4 mg/mL monothioglycerol.

Clause 1411. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 5.5 mg/mL monothioglycerol.

Clause 1501. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 9.5 mg/mL monothioglycerol.

Clause 1502. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 9.6 mg/mL monothioglycerol.

Clause 1503. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 9.7 mg/mL monothioglycerol.

Clause 1504. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 9.8 mg/mL monothioglycerol.

Clause 1505. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 9.9 mg/mL monothioglycerol.

Clause 1506. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 10 mg/mL monothioglycerol.

Clause 1601. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 10.1 mg/mL monothioglycerol.

Clause 1602. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 10.2 mg/mL monothioglycerol.

Clause 1603. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 10.3 mg/mL monothioglycerol.

Clause 1604. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 10.4 mg/mL monothioglycerol.

Clause 1605. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1001, comprising about 10.5 mg/mL monothioglycerol.

Clause 1701. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising from about 0.5 to about 2.5mg/mL monobasic sodium phosphate.

Clause 1702. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 0.5 mg/mL monobasic sodiumphosphate.

Clause 1703. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 0.6 mg/mL monobasic sodiumphosphate.

Clause 1704. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 0.7 mg/mL monobasic sodiumphosphate.

Clause 1705. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 0.8 mg/mL monobasic sodiumphosphate.

Clause 1706. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 0.9 mg/mL monobasic sodiumphosphate.

Clause 1707. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1 mg/mL monobasic sodiumphosphate.

Clause 1708. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.1 mg/mL monobasic sodiumphosphate.

Clause 1709. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.2 mg/mL monobasic sodiumphosphate.

Clause 1710. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.3 mg/mL monobasic sodiumphosphate.

Clause 1711. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.4 mg/mL monobasic sodiumphosphate.

Clause 1712. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.5 mg/mL monobasic sodiumphosphate.

Clause 1713. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.6 mg/mL monobasic sodiumphosphate.

Clause 1714. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.7 mg/mL monobasic sodiumphosphate.

Clause 1715. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.8 mg/mL monobasic sodiumphosphate.

Clause 1716. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 1.9 mg/mL monobasic sodiumphosphate.

Clause 1717. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 2 mg/mL monobasic sodiumphosphate.

Clause 1718. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 2.1 mg/mL monobasic sodiumphosphate.

Clause 1719. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 2.2 mg/mL monobasic sodiumphosphate.

Clause 1720. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 2.3 mg/mL monobasic sodiumphosphate.

Clause 1721. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 2.4 mg/mL monobasic sodiumphosphate.

Clause 1722. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1606, further comprising about 2.5 mg/mL monobasic sodiumphosphate.

Clause 1801. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising from about 5 to about 25 mg/mLdibasic sodium phosphate.

Clause 1802. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 5 mg/mL dibasic sodiumphosphate.

Clause 1803. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 6 mg/mL dibasic sodiumphosphate.

Clause 1804. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 7 mg/mL dibasic sodiumphosphate.

Clause 1805. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 8 mg/mL dibasic sodiumphosphate.

Clause 1806. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 9 mg/mL dibasic sodiumphosphate.

Clause 1807. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 10 mg/mL dibasic sodiumphosphate.

Clause 1808. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 11 mg/mL dibasic sodiumphosphate.

Clause 1809. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 12 mg/mL dibasic sodiumphosphate.

Clause 1810. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 13 mg/mL dibasic sodiumphosphate.

Clause 1811. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 14 mg/mL dibasic sodiumphosphate.

Clause 1812. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 15 mg/mL dibasic sodiumphosphate.

Clause 1813. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 16 mg/mL dibasic sodiumphosphate.

Clause 1814. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 17 mg/mL dibasic sodiumphosphate.

Clause 1815. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 18 mg/mL dibasic sodiumphosphate.

Clause 1816. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 19 mg/mL dibasic sodiumphosphate.

Clause 1817. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 20 mg/mL dibasic sodiumphosphate.

Clause 1818. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 21 mg/mL dibasic sodiumphosphate.

Clause 1819. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 22 mg/mL dibasic sodiumphosphate.

Clause 1820. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 23 mg/mL dibasic sodiumphosphate.

Clause 1821. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 24 mg/mL dibasic sodiumphosphate.

Clause 1822. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1722, further comprising about 25 mg/mL dibasic sodiumphosphate.

Clause 1901. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising from about 0.1 to about 1 mg/mLdisodium EDTA.

Clause 1902. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.1 mg/mL disodium EDTA.

Clause 1903. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.2 mg/mL disodium EDTA.

Clause 1904. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.3 mg/mL disodium EDTA.

Clause 1905. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.4 mg/mL disodium EDTA.

Clause 1906. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.5 mg/mL disodium EDTA.

Clause 1907. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.6 mg/mL disodium EDTA.

Clause 1908. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.7 mg/mL disodium EDTA.

Clause 1909. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.8 mg/mL disodium EDTA.

Clause 1910. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 0.9 mg/mL disodium EDTA.

Clause 1911. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1822, further comprising about 1 mg/mL disodium EDTA.

Clause 2001. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pHfrom about 7.5 to about 9.5.

Clause 2002. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pHfrom about 7.5 to about 8.

Clause 2003. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pHfrom about 8 to about 8.5.

Clause 2004. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pHfrom about 8.5 to about 9.

Clause 2101. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 7.5.

Clause 2102. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 7.6.

Clause 2103. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 7.7.

Clause 2104. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 7.8.

Clause 2105. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 7.9.

Clause 2106. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.

Clause 2107. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.1.

Clause 2108. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.2.

Clause 2109. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.3.

Clause 2110. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.4.

Clause 2111. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.5.

Clause 2112. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.6.

Clause 2113. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.7.

Clause 2114. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout, 8.8.

Clause 2115. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 8.9.

Clause 2116. The aqueous pharmaceutical formulation of any one ofclauses 101 to 1911, wherein the pharmaceutical formulation has a pH ofabout 9.

Clause 2201. The aqueous pharmaceutical formulation of any one ofclauses 1 to 2116, wherein the formulation comprises from no impuritiesto less than, or no more than 0.05% impurities upon formulation.

Clause 2202. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.04% impurities uponformulation.

Clause 2203. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.03% impurities uponformulation.

Clause 2204. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.02% impurities uponformulation.

Clause 2205. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.01% impurities uponformulation.

Clause 2206. The aqueous pharmaceutical formulation of any one ofclauses 1 to 2116, wherein the formulation comprises from no impuritiesto less than, or no more than 0.1% impurities upon formulation.

Clause 2207. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.09% impurities uponformulation.

Clause 2208. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.08% impurities uponformulation.

Clause 2209. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.07% impurities uponformulation.

Clause 2210. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.06% impurities uponformulation.

Clause 2211. The aqueous pharmaceutical formulation of any one ofclauses 1 to 2116, wherein the formulation comprises from no impuritiesto less than, or no more than 0.5% impurities upon formulation.

Clause 2212. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.45% impurities uponformulation.

Clause 2213. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.4% impurities uponformulation.

Clause 2214. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.35% impurities uponformulation.

Clause 2215. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.3% impurities uponformulation.

Clause 2216. The aqueous pharmaceutical formulation of any one ofclauses 1 to 2116, wherein the formulation comprises from no impuritiesto less than, or no more than 0.25% impurities upon formulation.

Clause 2217. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.2% impurities uponformulation.

Clause 2218. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.15% impurities uponformulation.

Clause 2219. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.14% impurities uponformulation.

Clause 2220. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2116, wherein the formulation comprises from noimpurities to less than, or no more than 0.13%, 0.12%, or 0.11%impurities upon formulation.

Clause 2301. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from noimpurities to less than, or no more than 0.07% impurities upon storageat 25° C. for about 3 months.

Clause 2302. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from noimpurities to less than, or no more than 0.06% impurities upon storageat 25° C. for about 3 months.

Clause 2303. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from noimpurities to less than, or no more than 0.05% impurities upon storageat 25° C. for about 3 months.

Clause 2304. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from noimpurities to less than, or no more than 0.04% impurities upon storageat 25° C. for about 3 months.

Clause 2305. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from noimpurities to less than, or no more than 0.03% impurities upon storageat 25° C. for about 3 months.

Clause 2306. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from noimpurities to less than, or no more than 0.02% impurities upon storageat 25° C. for about 3 months.

Clause 2307. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from noimpurities to less than, or no more than 0.01% impurities upon storageat 25° C. for about 3 months.

Clause 2308. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.07% impurities upon storageat 25° C. for about 3 months.

Clause 2309. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.06% impurities upon storageat 25° C. for about 3 months.

Clause 2310. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.05% impurities upon storageat 25° C. for about 3 months.

Clause 2311. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.04% impurities upon storageat 25° C. for about 3 months.

Clause 2312. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.03% impurities upon storageat 25° C. for about 3 months.

Clause 2313. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.02% impurities upon storageat 25° C. for about 3 months.

Clause 2314. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.1% impurities upon storage at25° C. for about 3 months.

Clause 2315. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.15% impurities upon storageat 25° C. for about 3 months.

Clause 2316. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.2% impurities upon storage at25° C. for about 3 months.

Clause 2317. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.25% impurities upon storageat 25° C. for about 3 months.

Clause 2318. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.3% impurities upon storage at25° C. for about 3 months.

Clause 2319. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2205, wherein the formulation comprises from 0.01%impurities to less than, or no more than 0.35%, 0.4%, or 0.5% impuritiesupon storage at 25° C. for about 3 months.

Clause 2401. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.20% impurities upon storage at 25° C. forabout 6 months.

Clause 2402. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.19% impurities upon storage at 25° C. forabout 6 months.

Clause 2403. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.18% impurities upon storage at 25° C. forabout 6 months.

Clause 2404. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.17% impurities upon storage at 25° C. forabout 6 months.

Clause 2405. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.16% impurities upon storage at 25° C. forabout 6 months.

Clause 2406. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.15% impurities upon storage at 25° C. forabout 6 months.

Clause 2407. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.14% impurities upon storage at 25° C. forabout 6 months.

Clause 2408. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.13% impurities upon storage at 25° C. forabout 6 months.

Clause 2409. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.12% impurities upon storage at 25° C. forabout 6 months.

Clause 2410. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.11% impurities upon storage at 25° C. forabout 6 months.

Clause 2411. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.10% impurities upon storage at 25° C. forabout 6 months.

Clause 2412. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.09% impurities upon storage at 25° C. forabout 6 months.

Clause 2413. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.08% impurities upon storage at 25° C. forabout 6 months.

Clause 2414. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from no impurities toless than, or no more than 0.07% impurities upon storage at 25° C. forabout 6 months.

Clause 2415. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.20% impurities upon storage at 25° C. forabout 6 months.

Clause 2416. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.19% impurities upon storage at 25° C. forabout 6 months.

Clause 2417. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.18% impurities upon storage at 25° C. forabout 6 months.

Clause 2418. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.17% impurities upon storage at 25° C. forabout 6 months.

Clause 2419. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.16% impurities upon storage at 25° C. forabout 6 months.

Clause 2420. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.15% impurities upon storage at 25° C. forabout 6 months.

Clause 2421. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.14% impurities upon storage at 25° C. forabout 6 months.

Clause 2422. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.13% impurities upon storage at 25° C. forabout 6 months.

Clause 2423. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.12% impurities upon storage at 25° C. forabout 6 months.

Clause 2424. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.11% impurities upon storage at 25° C. forabout 6 months.

Clause 2425. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.10% impurities upon storage at 25° C. forabout 6 months.

Clause 2426. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.09% impurities upon storage at 25° C. forabout 6 months.

Clause 2427. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.08% impurities upon storage at 25° C. forabout 6 months.

Clause 2428. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.07% impurities upon storage at 25° C. forabout 6 months.

Clause 2429. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.25% impurities upon storage at 25° C. forabout 6 months.

Clause 2430. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.3% impurities upon storage at 25° C. forabout 6 months.

Clause 2431. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.35% impurities upon storage at 25° C. forabout 6 months.

Clause 2432. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.4% impurities upon storage at 25° C. forabout 6 months.

Clause 2433. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.45% impurities upon storage at 25° C. forabout 6 months.

Clause 2434. The aqueous pharmaceutical formulation of any one of claims101 to 2307, wherein the formulation comprises from 0.01% impurities toless than, or no more than 0.5% impurities upon storage at 25° C. forabout 6 months.

Clause 2501. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2428, wherein upon storage at 40° C. for about 1 month,the formulation comprises from no impurities to less than, or no morethan 0.35% impurities.

Clause 2601. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2428, wherein upon storage at 40° C. for about 2 months,the formulation comprises from no impurities to less than, or no morethan 0.7% impurities.

Clause 2701. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2428, wherein upon storage at 40° C. for about 3 months,the formulation comprises from no impurities to less than, or no morethan 1.5% impurities.

Clause 2801. The aqueous pharmaceutical formulation of any one ofclauses 101 to 2428, wherein upon storage at 40° C. for about 6 months,the formulation comprises from no impurities to less than, or no morethan 2% impurities.

Clause 2901. The aqueous pharmaceutical formulation of any one ofclauses 2301 to 2801, wherein impurities concentration is measured uponstorage against at least one pharmaceutically acceptable surfaceselected from a stopper surface, a needle surface, a needle tip capsurface, a needle shield surface, a septa surface, a syringe plungersurface, a glass syringe surface, a plastic syringe surface, (e.g.neoprene, polyisoprene, silicone), an injector surface, a rubbersurface, and the like. Any surface may include any material known in theart, for example and without limitation, neoprene, polyisoprene,silicone, and the like.

Clause 3001. The aqueous pharmaceutical formulation of any one ofclauses 2201 to 2901, wherein impurities comprise hydrocortisone.

Clause 3002. The aqueous pharmaceutical formulation of any one ofclauses 2201 to 2901, wherein impurities consist essentially ofhydrocortisone.

Clause 3003. The aqueous pharmaceutical formulation of any one ofclauses 2201 to 2901, wherein the formulation comprises from nohydrocortisone to less than, or no more than 0.01% hydrocortisone; fromno hydrocortisone to less than, or no more than 0.025% hydrocortisone;from no hydrocortisone to less than, or no more than 0.05%hydrocortisone; from no hydrocortisone to less than, or no more than0.1% hydrocortisone; from no hydrocortisone to less than, or no morethan 0.15% hydrocortisone; from no hydrocortisone to less than, or nomore than 0.2% hydrocortisone; from no hydrocortisone to less than, orno more than 0.25% hydrocortisone; from no hydrocortisone to less than,or no more than 0.3% hydrocortisone; from no hydrocortisone to lessthan, or no more than 0.35% hydrocortisone; from no hydrocortisone toless than, or no more than 0.4% hydrocortisone; from no hydrocortisoneto less than, or no more than 0.45% hydrocortisone; or from nohydrocortisone to less than, or no more than 0.5% hydrocortisone.

Clause 3101. The aqueous pharmaceutical formulation of any one ofclauses 101 to 3003, wherein any formulation component concentration canbe expressed as % w/v, using a conversion factor of 1 mg/mL=0.1% w/v.

Clause 3201. A method of treating a disease, condition, or disorderalleviated by administering hydrocortisone or hydrocortisone sodiumphosphate in a patient in need thereof, the method comprisingadministering to the patient a therapeutically effective amount of theaqueous pharmaceutical formulation of any one of clauses 101 to 3101.

Clause 3301. The method of clause 3201, wherein the disease, condition,or disorder comprises one or more of swollen joints and/or tendons,painful joints and/or tendons, tennis elbow, and/or golfer's elbow.

Clause 3401. The method of clause 3201, wherein the disease, condition,or disorder comprises one or more of asthma, an allergic reaction,severe shock due to injury or infection, and/or or failure of theadrenal glands.

Clause 3501. The method of clause 3201, wherein the disease, condition,or disorder comprises inflammation.

Clause 3601. The method of clause 3201, wherein the disease, condition,or disorder comprises asthma, atopic dermatitis, contact dermatitis,drug hypersensitivity reactions, perennial or seasonal allergicrhinitis, serum sickness, and/or transfusion reactions.

Clause 3701. The method of clause 3201, wherein the disease, condition,or disorder comprises dermatologic diseases selected from bullousdermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides,pemphigus, severe erythema multiforme (Stevens-Johnson syndrome).

Clause 3801. The method of clause 3201, wherein the disease, condition,or disorder comprises endocrine disorders selected from primary orsecondary adrenocortical insufficiency, congenital adrenal hyperplasia,hypercalcemia associated with cancer, and/or nonsuppurative thyroiditis.

Clause 3901. The method of clause 3201, wherein the disease, condition,or disorder comprises gastrointestinal diseases.

Clause 4001. The method of clause 3201, wherein the disease, condition,or disorder comprises gastrointestinal diseases selected from regionalenteritis (systemic therapy) and ulcerative colitis.

Clause 4101. The method of clause 3201, wherein the disease, condition,or disorder comprises hematologic disorders selected from acquired(autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia(Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura inadults, pure red cell aplasia, selected cases of secondarythrombocytopenia.

Clause 4201. The method of clause 3201, wherein the disease, condition,or disorder comprises one or more of trichinosis with neurologic ormyocardial involvement, tuberculous meningitis with subarachnoid blockor impending block.

Clause 4301. The method of clause 3201, wherein the disease, condition,or disorder comprises neoplastic diseases.

Clause 4401. The method of clause 3201, wherein the disease, condition,or disorder comprises palliative management of leukemias and/orlymphomas.

Clause 4501. The method of clause 3201, wherein the disease, condition,or disorder comprises nervous system conditions selected from acuteexacerbations of multiple sclerosis; cerebral edema associated withprimary or metastatic brain tumor, or craniotomy.

Clause 4601. The method of clause 3201, wherein the disease, condition,or disorder comprises ophthalmic diseases selected from sympatheticophthalmia, uveitis and ocular inflammatory conditions.

Clause 4701. The method of clause 3201, wherein the disease, condition,or disorder comprises renal diseases.

Clause 4801. The method of clause 3201, wherein the disease, condition,or disorder comprises inducing diuresis or remission of proteinuria inidiopathic nephrotic syndrome or that due to lupus erythematosus.

Clause 4901. The method of clause 3201, wherein the disease, condition,or disorder comprises respiratory diseases selected from berylliosis,fulminating or disseminated pulmonary tuberculosis, idiopathiceosinophilic pneumonias, symptomatic sarcoidosis.

Clause 5001. The method of clause 3201, wherein the disease, condition,or disorder comprises rheumatic disorders selected from acute goutyarthritis; acute rheumatic carditis; ankylosing spondylitis; psoriaticarthritis; rheumatoid arthritis, including juvenile rheumatoidarthritis.

Clause 5101. The method of clause 3201, wherein the disease, condition,or disorder comprises dermatomyositis, temporal arteritis, polymyositis,and systemic lupus erythematosus.

Clause 5201. The method of clause 3201, wherein the disease, condition,or disorder comprises adrenal insufficiency selected from primaryadrenal insufficiency, acute adrenal insufficiency, and secondaryadrenal insufficiency.

A number of patent and non-patent publications are cited herein in orderto describe the state of the art to which this invention pertains. Theentire disclosure of each of these publications is incorporated byreference herein.

The following examples describe the invention in further detail. Theseexamples are provided for illustrative purposes only, and should in noway be considered as limiting the invention.

EXAMPLES Example 1

Antioxidants, chelating agent, buffer agents used in the stability studyare listed in the following table:

Inactive ingredients used in the formulation development;

TABLE 1 Level FDA IIG Inactive Quality used in Limit ingredientFunctionality Standard the study for IM Edetate Chelating agent USP0.02% w/v   10% w/v disodium Sodium sulfite Antioxidant USP  0.2% w/v 0.2% w/v Sodium Antioxidant USP-NF  0.2% w/v  0.2% w/v formaldehydesulfoxylate Monothioglycerol Antioxidant USP-NF  0.5% w/v  0.5% w/vAscorbic acid Antioxidant USP  0.2% w/v  0.2% w/v Methionine AntioxidantUSP 0.05% w/v  0.05% w/v Niacinamide Stabilizer USP  2.5% w/v  2.5% w/vCreatinine Stabilizer USP  0.8% w/v  0.8% w/v Hydroxylpropyl StabilizerUSP-NF   10% w/v 33.33% w/v beta cyclodextrin Sodium Buffer agent USP-NF 0.1-0.8% 27.8% phosphate dibasic Sodium Buffer agent USP-NF 0.01-0.08%2.56% phosphate monobasic

Procedure for formulation preparation: add ˜90% of water to a container;turn on the mixer; add Monobasic sodium phosphate anhydrous, Dibasicsodium phosphate anhydrous, Disodium EDTA, an antioxidant, or a thirdstabilizer, use a portion of water to rinse if needed, mix for at least15 min or until dissolved; weigh hydrocortisone sodium phosphate andcharge to the container from previous step, mix for at least 30 min anduntil dissolved; measure pH, adjust pH to approx. 8.0 using 0.1 N HCl or0.1 N NaOH; Q.S. to final volume (weight) using water, mix for at least15 min.

A stability indicating HPLC method was developed, suitable formonitoring hydrolysis of hydrocortisone sodium phosphate and otherdegradations based on literature methods for hydrocortisone prodrugs andother similar products. A detailed description of the HPLC method withinformation such as chromatography conditions and sample preparation, isdescribed herein. in 5.0 Analytical method development

Primary Packaging Materials:

Material Description Syringe Barrel Ompi Article #7600007.6977, SyringeEZ-Fill 1 mL Long, 22G 5/8 3B, NS 4800GS, NE160, EB, IUP Stopper WestStoppers Item # 10149656, Article 2340 4432/50 Gry B2-40 Westar RU

The pH effect was evaluated for Formulations F #1 to F #4 at 13.42%hydrocortisone sodium phosphate with disodium edetate and sodiumformaldehyde included at level typically used in injectable products.The effect of drug concentration on stability was studied in F #5, whichhas a concentration at 6.71% (50 mg/mL hydrocortisone) in comparison to13.42% (100 mg/mL hydrocortisone) for the other formulations.

Prototype formulations to evaluate pH and concentration:

TABLE 2 Ingredient F#1 F#2 F#3 F#4 F#5 Hydrocortisone 13.42% 13.42%13.42% 13.42% 6.71% sodium phosphate (w/v) Monobasic   0.1%   0.1%  0.1%   0.1%  0.1% sodium phosphate anhydrous Dibasic  1.09%  1.09% 1.09%  1.09% 1.09% sodium phosphate anhydrous Disodium  0.02%  0.02% 0.02%  0.02% 0.02% EDTA Sodium   0.2%   0.2%   0.2%   0.2%  0.2%formaldehyde sulfoxylate Sodium q.s. to pH q.s. to pH q.s. to pH q.s. topH q.s. to pH hydroxide/HC 7.0 7.5 8.0 8.5 8.0 1 Water q.s. to q.s. toq.s. to q.s. to q.s. to 1 mL 1 mL 1 mL 1 mL 1 mL

A second group of formulations were designed to study alternativeantioxidants to sodium formaldehyde sulfoxylate, such as sodium sulfite,monothioglycerol, ascorbic acid, and methionine, whether betterstabilization effect can be achieved (F #6-9):

Prototype formulations to evaluate the effect of antioxidants:

TABLE 3 Ingredient F #6 F#7 F#8 F#9 Hydrocortisone 13.42% 13.42% 13.42%13.42% sodium phosphate Monobasic sodium  0.1%  0.1%  0.1%  0.1%phosphate anhydrous Dibasic sodium  1.09%  1.09%  1.09%  1.09% phosphateanhydrous Disodium EDTA  0.02%  0.02%  0.02%  0.02% Sodium sulfite  0.2% Monothioglycerol   0.5% Ascorbic acid   0.2% Methionine  0.05%Sodium q.s to pH q.s to pH q.s to pH q.s to pH hydroxide/HCl 8.0 8.0 8.08.0 Water q.s to 1 mL q.s to 1 mL q.s to 1 mL q.s to 1 mL

As disclosed by U.S. Pat. No. 2,970,944, incorporated herein in itsentirety, the stability of aqueous steroid phosphates includinghydrocortisone sodium phosphates can be increased by incorporation of asmall amount of a nitrogen containing compound such as niacinamide andcreatinine. The main instability for steroid phosphates is the formationof precipitate during storage, which is due to the hydrolysis to formfree hydrocortisone with much less aqueous solubility. It is possiblethat niacinamide and creatinine increase the solubility ofhydrocortisone and thus, prevent precipitation after formation fromhydrolysis.

The purpose to study Formulation F #10 to F #13 was to evaluate whethersolubilizing agents like niacinamide, creatinine, hydroxylpropyl betacyclodextrin can stabilize hydrocortisone sodium phosphate injection tomaintain as clear solutions during stability test.

Prototype formulations to evaluate solubilizing agents

TABLE 4 Ingredient F #10 F #11 F #12 F #13 F #14 F #15 Hydrocortisone13.42% w/v 13.42% w/v 13.42% w/v 13.42% w/v 13.42% w/v 13.42% w/v sodiumphosphate Monobasic  0.1% w/v  0.1% w/v  0.1% w/v  0.1% w/v  0.1% w/v 0.1% w/v sodium phosphate anhydrous Dibasic  1.09% w/v  1.09% w/v 1.09% w/v  1.09% w/v  1.09% w/v  1.09% w/v sodium phosphate anhydrousDisodium  0.02% w/v  0.02% w/v  0.02% w/v  0.02% w/v  0.02% w/v  0.02%w/v EDTA Sodium  0.2% w/v  0.2% w/v  0.2% w/v  0.2% w/v  0.2% w/v  0.2%w/v formaldehyde sulfoxylate Creatinine 0.8% w/v Niacinamide 2.5% w/vHydroxypropyl  5.0% w/v  10.0% w/v beta cyclodextrin Lactobionic  0.2%w/v acid Sodium q.s to pH q.s to pH q.s to pH q.s to pH q.s to pH q.s topH hydroxide/HCl 8.0 8.0 8.0 8.0 8.0 8.0 Water q.s to 1 mL q.s to 1 mLq.s to 1 mL q.s to 1 mL q.s to 1 mL q.s to 1 mL

The needle shield in PFS is permeable to oxygen. Without wishing to bebound by any particular theory, it is believed that the use of barrierpackaging such as foil pouch has the potential to enhance the stabilityof hydrocortisone sodium phosphate injection in PFS. The foil pouch tobe evaluated is from Glenroy with film structure EFS 477-001. Two setsof formulation F #8 and F #15 PFS were packed with foil pouch purgedwith nitrogen, one PFS per pouch, while another set were packed the foilpouch with StabilOx oxygen scavenger, one PFS/two packs of oxygenscavenger per pouch, as described herein, to evaluate whether barrierpackaging offer any stabilizing effect.

Specification of Glenroy foil pouch:

Criteria Details Product Name Glenroy Foil Pouch Supplier Item # EFS477-001 Dimensions Width − 3.246-inch, Length − 9.75 inch, and Seal − ⅜inch Material Construction Coated Polyester (PET) − 0.48 mm, LDPE white− 0.75 mm, Aluminum foil − 0.5 mm, HPC − 0.75 mm, LLDPE − 1.25 mm

Details of StabilOx, D100-H60 Oxygen Absorber Packets:

TABLE 5 Criteria Details Product Name StabilOx ®, D-100-H60, is anoxygen absorbing packet in cut strip form. Part Number 02-02937CG10DESCRIPTION StabilOx ®, D-100-H60 oxygen absorbers are designed toabsorb a minimum of 100 cc of oxygen for modified atmosphere packagingof dry or semi-moist products with water activity less than 0.7 intendedfor storage and distribution at ambient or refrigerated temperaturesdown to 30 degrees F. The rate of absorption is dependent upon theequilibrium relative humidity and the composition of the atmospherewithin the package. Physical Attributes 0.76” wide ± 0 .04” X 1.83” long± 0.07”, The D-100-H60 is active in air and will begin to react withinone-half hour after removal of the protective barrier pouch MATERIALSProduct contact surface is Tyvek ® and suitable for direct food contact

Study of packaging control on stability of HCP injection in PFS:

TABLE 6 Sublot# F#-A F#-B F#-C Formulation Formulation F#8 and F#15Pouch None One PFS, Purging One PFS, Two nitrogen, pouching oxygenscavengers, Pouching

All the formulations were prepared together, filled in PFS and wereplaced on stability. There are different sets of formulations.Formulations for each set were prepared on a separate day, PFS werefilled and the zero time analysis was conducted on the next day.Information on actual composition of 15 prototype formulations isdescribed herein.

Stability program for the stability work are defined below:

TABLE 7 Storage Intervals Contingency Condition Initial 1 M 2 M 3 M 6 M9 M 12 M 18 M 24 M samples 25° C. X X X (X) (X) (X) (X) 5 40° C. X X X X— — 2 X = Appearance, Color/Clarity, pH, Assay and Related substances(X) The decision to analyze these samples is to be made at 6 M timepoint

Following HPLC method was developed to determine the potency ofHydrocortisone sodium Phosphate and the area % of Hydrocortisoneimpurity and other unknown impurities in Hydrocortisone sodium Phosphateinjection. This method employs High Performance Liquid Chromatography(HPLC) to determine the potency of Hydrocortisone sodium Phosphate andthe area % of Hydrocortisone impurity and other unknown impurities inHydrocortisone sodium Phosphate injection.

Equipment and Materials:

-   -   HPLC: Waters Alliance 2695 with Waters 2998 PDA detector; a data        handling system with Empower 2 software.

Reagents:

-   -   1) Trifluoroacetic acid    -   2) Distilled water    -   3) Acetonitrile, HPLC grade    -   4) Hydrocortisone sodium Phosphate standard (in-house)    -   5) Hydrocortisone impurity standard (in-house)    -   Chromatography conditions:    -   Column: Waters Sunfire C18, 250×4.6 mm, 5 μm    -   Column temperature: Ambient    -   Mobile Phase A: 0.2% v/v TFA in water    -   Mobile Phase B:0.2% v/v TFA in ACN    -   Diluent: Water:ACN (80:20)    -   Pump wash & Needle wash: Diluent    -   Flow Rate: 1.5 mL/min    -   Injection volume: 10 μL    -   Run time: 45 minutes    -   Detection wavelength: 254 nm    -   Elution technique: Gradient (Linear):

TABLE 8 Time in Minutes % Mobile Phase A % Mobile Phase B 0.00 85 1510.00 85 15 22.40 55 45 38.00 30 70 38.10 85 15 45.00 85 15

Preparation of Hydrocortisone Sodium Phosphate Standard Solution:

Prepared a 0.5 mg/mL solution of Hydrocortisone Sodium Phosphate usingthe diluent. Weighed required amount of standard in a clean empty anddry volumetric flask. Added ˜80% volume diluent to the flask to dissolvestandard. Sonicated, if necessary. Made up volume to the mark usingdiluent, mixed well and used in analysis. Prepared standards induplicate.

Preparation of Hydrocortisone Impurity Stock Solution:

Prepared a stock solution of Hydrocortisone impurity using ACN forqualitative purpose.

Preparation of Peak Identification Solution:

Spiked the Hydrocortisone impurity stock solution to one of the twoHydrocortisone Sodium Phosphate standard solutions separately to preparethe Peak Identification solution. Injected this solution in HPLCsequence to find out the peak shape, peak symmetry and actual retentiontimes of Hydrocortisone Sodium Phosphate and Hydrocortisone impurity onChromatogram. Used this solution for qualitative purpose only.

Preparation of Hydrocortisone Sodium Phosphate Injection Test Solution:

Prepared a test solution of Hydrocortisone Sodium Phosphate injection indiluent. Weighed required amount of formulation equivalent to 0.5 mg/mLof Hydrocortisone Sodium Phosphate in a clean empty and dry volumetricflask. Added ˜80% volume diluent to the flask to dissolve formulation.Sonicated, if necessary. Made up volume to the mark using diluent, mixedwell and used in analysis. Prepared test solutions for zero timeanalysis in duplicate.

System suitability criteria for analysis:

1) Accuracy of response between 2 HCP standards should be in 98-102%.The accuracy of response is calculated using following equation:

${\%\mspace{14mu}{Accuracy}\mspace{14mu}{of}\mspace{14mu}{responce}} = {\left( \frac{{Peak}\mspace{14mu}{area}\mspace{14mu}{of}\mspace{14mu}{Std}\mspace{14mu} 2}{{Peak}\mspace{14mu}{area}\mspace{14mu}{of}\mspace{14mu}{Std}\mspace{14mu} 1} \right) \times \left( \frac{{Concentration}\mspace{14mu}{of}\mspace{14mu}{Std}\mspace{14mu} 1}{{Concentration}\mspace{14mu}{of}\mspace{14mu}{Std}\mspace{14mu} 2} \right) \times 100}$

2) % relative standard deviation of peak areas for 5 repeated injectionsof HCP standard should be less than 2%.

3) Chromatogram of blank (Diluent) should be without unwanted peaks orhumps.

4) Note the retention times of Hydrocortisone Sodium Phosphate andHydrocortisone impurity at zero time analysis. These retention timesshould not change more than 1 minute range (i.e. ±0.5 minutes)

A typical chromatogram of HCP using the developed analytical method isas depicted in FIG. 2.

15 formulations were evaluated under stability study at 40° C. and 25°C. in PFS, to evaluate pH effect, combination of antioxidants, for 6months. Results from stability data at 40° C. and 25° C.:

-   -   Optimum pH range 7.5 to 8.5, in agreement with USP monograph        spec    -   Combinations of EDTA/Monothiolglycerol, EDTA/sulfite show better        stability than the combination of EDTA/Rongalite, which is        covered by a U.S. Pat. No. 10,456,355, incorporated in its        entirety herein    -   The addition of a third stabilizer, creatine significantly        improve the stability of formulation containing EDTA/Rongalite    -   The addition of creatinine as the third stability does not offer        noticeable further stability improvement to        EDTA/monothiolglycerol, EDTA/sulfite combination

Three lead formulations having much better stability than the U.S. Pat.No. 10,456,355 formulation, with ˜60% less degradation after 6 mon at40° C., and with extrapolated shelf life at 24 months based on currentstability trend (see FIG. 1). Formulation at 50 mg/mL has a viscosityclose to water and injection time about 3 second for 2 mL fill. Additionof creatinine as the third stabilizer for EDTA/MTG and EDTA/sulfiteoffering no noticeable improvement based on 3 month data.

TABLE 9 Formulation Ingredient Comment F#3 EDTA/Rongalite U.S. Pat. No.10,456,355 F#10 EDTA/Rongalite/ Improved on patented Creatinineformulation F#6 EDTA/sulfite Sulfite allergic concern F#7 EDTA/MTG Bestcandidate

TABLE 10 Total impurities at 25° C.: Time Rongalite/ Rongalite/EDTA/Sulfite/ MTG/ (mon) EDTA Creatinine EDTA EDTA 0 0.00% 0.00% 0.09% 0.00%3 0.20% 0.09% 0.04% 0.06% 6 0.61% 0.12% 0.21% 0.12%

TABLE 11 Com- FDA position inactive Com- per ingredient position unitdose, database Ingredients Function per 1 mL 2 mL limit HydrocortisoneActive 67.1 mg 134.2 mg — sodium phosphate ingredient (50 mg (100 mghydro- hydrocortisone) cortisone) Monobasic Buffer  1.0 mg  2.0 mg 1.2%w/v, sodium phosphate agent IM anhydrous Dibasic sodium Buffer 10.9 mg21.8 mg 1.75% w/v, phosphate agent IM anhydrous Disodium edetateChelating  0.2 mg  0.4 mg 10% w/v, agent IM Monothioglycerol Antioxidant 5.0 mg 10.0 mg 0.5% w/v, IM Sodium pH adjustor Q.S pH Q.S pH —hydroxide/HCl (appr (appr 8.0) 8.0) Water Solvent Q.S. to Q.S. to — 1 mL1 mL

To develop this method, Hydrocortisone sodium phosphate API was keptunder stress conditions. These stress conditions included treatment with0.1 N HCl, 0.1 N NaOH and dry heat. This was performed to investigatethe nature of API and its compatibility with the stress conditions. Italso helped generate degradation products to assess the specificity ofthe HPLC method under development. Information on degradation productsand the conditions used to generate them was used to optimize the methodfor better resolution of such degradation products on chromatogram.FIGS. 3A-3C show chromatograms of HCP under stress conditions.

Forced degradation of HCP under 3 different stress conditions resultedin formation of Hydrocortisone, other common degradants. The proportionsin which the degradants formed depended on the stress condition. Stressstudies performed on the API were done for qualitative purpose only.

Preparation of HCP Prototype Formulations.

Following Tables 12 to 26 contain actual composition of HCP prototypeformulations prepared for this study. Each Table also has values fordensity for each formulation prepared. Density has been calculated usinggravimetry in the flask used to prepare formulation.

TABLE 12 Composition of HCP Formulation #1 Description: Drugconcentration: 13.42%, pH 7.0 Ingredient Amount w/v Amount/50 mL Actualamount Hydrocortisone sodium 13.42% 6.71 g 6.7110 g phosphate (w/v)Monobasic sodium   0.1% 50 mg 50.3 mg phosphate anhydrous Dibasic sodium 1.09% 545 mg 545.4 mg phosphate anhydrous Disodium EDTA  0.02% 10 mg10.1 mg Sodium formaldehyde   0.2% 100 mg 102.2 mg sulfoxylate Sodiumhydroxide/HCl q.s. to pH 7.0 q.s. to pH 7.0 7.08 Water q.s. to 1 mL q.s.to 50 mL q.s. to 50 mL Density: 1.0602 g/mL

TABLE 13 Composition of HCP Formulation #2 Description: Drugconcentration: 13.42%, pH 7.5 Ingredient Amount w/v Amount/50 mL Actualamount Hydrocortisone sodium phosphate 13.42% 6.71 g 6.7100 g (w/v)Monobasic sodium phosphate 0.1% 50 mg 50.0 mg anhydrous Dibasic sodiumphosphate 1.09% 545 mg 545.1 mg anhydrous Disodium EDTA 0.02% 10 mg 9.8mg Sodium formaldehyde 0.2% 100 mg 100.1 mg sulfoxylate Sodiumhydroxide/HCl q.s. to pH 7.5 q.s. to pH 7.5 7.55 Water q.s. to 1 mL q.s.to 50 mL q.s. to 50 mL Density: 1.0587 g/mL

TABLE 14 Composition of HCP Formulation #3 Description: Drugconcentration: 13.42%, pH 8.0 Ingredient Amount w/v Amount/50 mL Actualamount Hydrocortisone sodium 13.42% 6.71 g 6.7102 g phosphate (w/v)Monobasic sodium 0.1% 50 mg 50.9 mg phosphate anhydrous Dibasic sodium1.09% 545 mg 545.6 mg phosphate anhydrous Disodium EDTA 0.02% 10 mg 10.0mg Sodium formaldehyde 0.2% 100 mg 102.0 mg sulfoxylate Sodiumhydroxide/HCl q.s. to pH 8.0 q.s. to pH 8.0 8.03 Water q.s. to 1 mL q.s.to 50 mL q.s. to 50 mL Density: 1.0597 g/mL

TABLE 15 Composition of HCP Formulation #4 Description: Drugconcentration: 13.42%, pH 8.5 Ingredient Amount w/v Amount/50 mL Actualamount Hydrocortisone sodium 13.42% 6.71 g 6.7107 g phosphate (w/v)Monobasic sodium 0.1% 50 mg 50.7 mg phosphate anhydrous Dibasic sodium1.09% 545 mg 544.9 mg phosphate anhydrous Disodium EDTA 0.02% 10 mg 10.4mg Sodium formaldehyde 0.2% 100 mg 99.9 mg sulfoxylate Sodiumhydroxide/HCl q.s. to pH 8.5 q.s. to pH 8.5 8.50 Water q.s. to 1 mL q.s.to 50 mL q.s. to 50 mL Density: 1.0602

TABLE 16 Composition of HCP Formulation #5 Description: Drugconcentration: 6.71%, pH 8.0 Ingredient Amount w/v Amount/50 mL Actualamount Hydrocortisone sodium 6.71% 3.355 g 3.3556 g phosphate (w/v)Monobasic sodium 0.1% 50 mg 50.2 mg phosphate anhydrous Dibasic sodium1.09% 545 mg 544.9 mg phosphate anhydrous Disodium EDTA 0.02% 10 mg 9.9mg Sodium formaldehyde 0.2% 100 mg 100.7 mg sulfoxylate Sodiumhydroxide/HCl q.s. to pH 8.0 q.s. to pH 8.0 8.03 Water q.s. to 1 mL q.s.to 50 mL q.s. to 50 mL Density: 1.0329 g/mL

TABLE 17 Composition of HCP Formulation #6 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Sodium sulfite IngredientAmount w/v Amount/50 mL Actual amount Hydrocortisone sodium phosphate13.42% 6.71 g 6.7107 g (w/v) Monobasic sodium phosphate 0.1% 50 mg 50.4mg anhydrous Dibasic sodium phosphate 1.09% 545 mg 545.2 mg anhydrousDisodium EDTA 0.02% 10 mg 10.0 mg Sodium sulfite 0.2% 100 mg 100.0 mgSodium hydroxide/HCl q.s. to pH 8.0 q.s. to pH 8.0 8.04 Water q.s. to 1mL q.s. to 50 mL q.s. to 50 mL Density: 1.0584 g/mL

TABLE 18 Composition of HCP Formulation #7 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Monothioglycerol IngredientAmount w/v Amount/50 mL Actual amount Hydrocortisone sodium phosphate13.42% 6.71 g 6.7100 g (w/v) Monobasic sodium phosphate 0.1% 50 mg 50.5mg anhydrous Dibasic sodium phosphate 1.09% 545 mg 545.2 mg anhydrousDisodium EDTA 0.02% 10 mg 10.3 mg Monothioglycerol 0.5% 250 mg 256.6 mgSodium hydroxide/HCl q.s. to pH 8.0 q.s. to pH 8.0 8.15 Water q.s. to 1mL q.s. to 50 mL q.s. to 50 mL Density: 1.0600 g/mL

TABLE 19 Composition of HCP Formulation #8 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Ascorbic Acid. IngredientAmount w/v Amount/200 mL Actual amount Hydrocortisone sodium phosphate13.42% 26.84 g 26.838 g (w/v) Monobasic sodium phosphate 0.1% 200 mg200.1 mg anhydrous Dibasic sodium phosphate 1.09% 2.180 g 2.1806 ganhydrous Disodium EDTA 0.02% 40 mg 40.0 mg Ascorbic acid 0.2% 400 mg400.2 mg Sodium hydroxide/HCl q.s. to pH 8.0 q.s. to pH 8.0 7.98 Waterq.s. to 1 mL q.s. to 200 mL q.s. to 200 mL Density: 1.0598 g/mL

Syringes of HCP Formulation #8 was divided into 3 sublots HCP F #8A, HCPF #8B and HCP F #8C.

HCP F #8A syringes were kept unpouched.

HCP F #8B syringes were pouched with Nitrogen purging.

HCP F #8C syringes were pouched with 2 Oxygen scavengers (no Nitrogenpurging).

TABLE 20 Composition of HCP Formulation #9 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Methoinine. Ingredient Amountw/v Amount/50 mL Actual amount Hydrocortisone sodium phosphate 13.42%6.71 g 6.7113 g (w/v) Monobasic sodium phosphate 0.1% 50 mg 50.0 mganhydrous Dibasic sodium phosphate 1.09% 545 mg 545.0 mg anhydrousDisodium EDTA 0.02% 10 mg 10.2 mg Methionine 0.05% 25 mg 25.1 mg Sodiumhydroxide/HCl q.s. to pH 8.0 q.s. to pH 8.0 8.14 Water q.s. to 1 mL q.s.to 50 mL q.s. to 50 mL Density: 1.0592 g/mL

TABLE 21 Composition of HCP Formulation #10 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Creatinine. Ingredient Amountw/v Amount/50 mL Actual amount Hydrocortisone sodium phosphate 13.42%6.71 g 6.7109 g (w/v) Monobasic sodium phosphate 0.1% 50 mg 50.2 mganhydrous Dibasic sodium phosphate 1.09% 545 mg 545.5 mg anhydrousDisodium EDTA 0.02% 10 mg 10.0 mg Sodium formaldehyde 0.2% 100 mg 101.0mg sulfoxylate Creatinine 0.8% 400 mg 400.2 mg Sodium hydroxide/HCl q.s.to pH 8.0 q.s. to pH 8.0 8.09 Water q.s. to 1 mL q.s. to 50 mL q.s. to50 mL Density: 1.0610 g/mL

TABLE 22 Composition of HCP Formulation #11 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Niacinamide. Ingredient Amountw/v Amount/50 mL Actual amount Hydrocortisone sodium phosphate 13.42%6.71 g 6.7107 g (w/v) Monobasic sodium phosphate 0.1% 50 mg 50.0 mganhydrous Dibasic sodium phosphate 1.09% 545 mg 545.2 mg anhydrousDisodium EDTA 0.02% 10 mg 10.4 mg Sodium formaldehyde 0.2% 100 mg 100.9mg sulfoxylate Niacinamide 2.5% 1.25 g 1.2504 g Sodium hydroxide/HClq.s. to pH 8.0 q.s. to pH 8.0 7.98 Water q.s. to 1 mL q.s. to 50 mL q.s.to 50 mL Density: 1.0655 g/mL

TABLE 23 Composition of HCP Formulation #12 Description: Drugconcentration: 13.42%, pH 8.0, Effect of 5% HP-β-cyclodextrin.Ingredient Amount w/v Amount/50 mL Actual amount Hydrocortisone sodium13.42% 6.71 g 6.7106 g phosphate (w/v) Monobasic sodium  0.1% 50 mg 50.0mg phosphate anhydrous Dibasic sodium  1.09% 545 mg 545.2 mg phosphateanhydrous Disodium EDTA  0.02% 10 mg 9.9 mg Sodium formaldehyde  0.2%100 mg 100.9 mg sulfoxylate HP-β-cyclodextrin  5.0% 2.5 g 2.5002 gSodium hydroxide/HCl q.s. to q.s. to 8.06 pH 8.0 pH 8.0 Water q.s. toq.s. to q.s. to 1 mL 50 mL 50 mL Density: 1.0749 g/mL

TABLE 24 Composition of HCP Formulation #13 Description: Drugconcentration: 13.42%, pH 8.0, Effect of 10% HP-β-cyclodextrin.Ingredient Amount w/v Amount/50 mL Actual amount Hydrocortisone sodium13.42% 6.71 g 6.7098 g phosphate (w/v) Monobasic sodium 0.1% 50 mg 50.1mg phosphate anhydrous Dibasic sodium 1.09% 545 mg 544.8 mg phosphateanhydrous Disodium EDTA 0.02% 10 mg 10.3 mg Sodium formaldehyde 0.2% 100mg 100.9 mg sulfoxylate HP-β-cyclodextrin 10.0% 5.0 g 5.0007 g Sodiumhydroxide/HCl q.s. to pH 8.0 q.s. to pH 8.0 7.98 Water q.s. to 1 mL q.s.to 50 mL q.s. to 50 mL Density: 1.0883 g/mL

TABLE 25 Composition of HCP Formulation #14 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Lactbionic acid. Amount/ ActualIngredient Amount w/v 50 mL amount Hydrocortisone sodium 13.42% 6.71 g6.7100 g phosphate (w/v) Monobasic sodium  0.1% 50 mg 49.9 mg phosphateanhydrous Dibasic sodium  1.09% 545 mg 545.3 mg phosphate anhydrousDisodium EDTA  0.02% 10 mg 9.8 mg Sodium formaldehyde  0.2% 100 mg 101.8mg sulfoxylate Lactobionic Acid  0.2% 100 mg 100.4 mg Sodiumhydroxide/HCl q.s. to q.s. to 8.04 pH 8.0 pH 8.0 Water q.s. to 1 mL q.s.to q.s. to 50 mL 50 mL Density: 1.0607 g/mL

TABLE 26 Composition of HCP Formulation #15 (previously HCP F #3)Description: Drug concentration: 13.42%, pH 8.0. Ingredient Amount w/vAmount/50 mL Actual amount Hydrocortisone sodium 13.42% 28.840 g 26.838g phosphate (w/v) Monobasic sodium 0.1% 200 mg 200.3 mg phosphateanhydrous Dibasic sodium 1.09% 2.180 mg 2.1806 mg phosphate anhydrousDisodium EDTA 0.02% 40 mg 40.3 mg Sodium formaldehyde 0.2% 400 mg 402.0mg sulfoxylate Sodium hydroxide/HCl q.s. to pH 8.0 q.s. to pH 8.0 7.98Water q.s. to 1 mL q.s. to 2000 mL q.s. to 200 mL Density: 1.0603 g/mL

Syringes of HCP Formulation #15 was divided into 3 sublots HCP F #15A,HCP F #15B and HCP F #15C.

HCP F #15A syringes were kept unpouched.

HCP F #15B syringes were pouched with Nitrogen purging.

HCP F #15C syringes were pouched with 2 Oxygen scavengers (no Nitrogenpurging).

Stability data for HCP prototypeformulations.

Following Tables 27 to 45 contain stability profile for HCP formulations1 to 15 up to 6 month storage at 25° C. and 40° C. It has data on %assay, % peak area of HCP, % area of known impurity Hydrocortisone andother unknown impurities. Please note that the reporting threshold forHydrocortisone impurity have been kept as 0.01% as it is a majordegradant. For other impurities, it has been kept as 0.05% onchromatogram. Once the identification and qualification these unknownimpurities is completed, a suitable identification threshold andqualification threshold can be used in future studies.

Stability data on following 4 unknown impurities have been kept in thetable according to their formation. The sum of total other unknownimpurities, which are lower in amounts have been taken into account when% peak area of HCP was calculated. Following formulas can be used tocalculate impurities.

Sum of total impurities=100−% peak area of HCP

Sum of total unknown imp=100−(% peak of HCP+% peak of Hydrocortisoneimp)

Sum of other unknown imp=100−(sum of % peak of HCP,Hydrocortisone & imp1 to 4)

Impurity 1 in the stability data tables has been identified as the peakof a degradation product that elutes at 5.00 minutes on chromatogram.The relative retention time for this impurity is 0.26. This impurity wasobserved during the alkali hydrolysis of HCP using 0.1N NaOH duringmethod development. This impurity was also prevalent from early stagesof the accelerated stability condition (40° C.) in formulations that hadSodium formaldehyde sulfoxylate in their composition as an antioxidant.

Impurity 2 in the stability data tables has been identified as the peakof a degradation product that elutes at 15.07 minutes on chromatogram.The relative retention time for this impurity is 0.79. This impurity wasnot observed during forced degradation of HCP in method development.

Impurity 3 in the stability data tables has been identified as the peakof a degradation product that elutes at 17.25 minutes on chromatogram.The relative retention time for this impurity is 0.91. This impurity wasobserved during the alkali hydrolysis of HCP using 0.1 N NaOH duringmethod development.

Impurity 4 in the stability data tables has been identified as the peakof a degradation product that elutes at 23.64 minutes on chromatogram.The relative retention time for this impurity is 1.24. This impurity wasobserved during the thermal degradation of HCP using dry heat duringmethod development.

Amounts of these 4 unknown impurities are more in formulations comparedto those of other unknown impurities. Further investigation should bedone on such unknown impurities to reduce the risk of their formation infuture formulations.

TABLE 21 Stability profile of HCP Formulation #1 Description: Drugconcentration: 13.42%, pH 7.0 % % % % % % % Impurity 1 Impurity 2Impurity 3 Impurity 4 Hydrocortisone Peak pH of Duration Assay RRT 0.26RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 area formulation Storage condition:25° C. Initial 101.27 — — — — 0.0 100.0 7.08  3 M 97.53 — — — 0.16 0.1899.6 7.08  6 M 95.30 — — — 0.28 0.28 99.2 7.04  9 M 12 M 18 M 24 MStorage condition: 40° C. Initial 101.27 — — — — 0.0 100.0 7.08  1 M100.64 — — — 0.21 0.70 98.3 7.05  2 M 91.53 0.13 0.11 0.05 0.93 0.8796.5 6.99  3 M 89.05 0.24 0.14 0.06 1.50 0.92 94.9 7.10  6 M 80.32 0.630.23 0.14 3.42 1.40 89.6 7.04

TABLE 28 Stability profile of HCP Formulation #2 Description: Drugconcentration: 13.42%, pH 7.5 % % % % % % % Impurity 1 Impurity 2Impurity 3 Impurity 4 Hydrocortisone Peak pH of Duration Assay RRT 0.26RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 area formulation Storage condition:25° C. Initial 100.85 — — — — 0.0 100.0 7.61  3 M 95.53 — — — 0.07 0.0899.8 7.56  6 M 95.80 — 0.08 — 0.10 0.10 99.5 7.51  9 M 12 M 18 M 24 MStorage condition: 40° C. Initial 100.85 — — — — 0.0 100.0 7.61  1 M96.49 — 0.13 0.11 0.13 0.31 98.9 7.52  2 M 95.21 0.27 0.22 0.09 0.440.30 97.7 7.50  3 M 82.30 0.45 0.24 0.16 0.55 0.25 97.4 7.54  6 M 86.721.36 0.41 0.22 1.36 0.41 94.1 7.44

TABLE 29 Stability profile of HCP Formulation #3 Description: Drugconcentration: 13.42%, pH 8.0 % % % % % % % Impurity 1 Impurity 2Impurity 3 Impurity 4 Hydrocortisone Peak pH of Duration Assay RRT 0.26RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 area formulation Storage condition:25° C. Initial 100.62 — — — — 0.0 100.0 8.17  3 M 95.08 — 0.10 — — 0.0499.8 7.97  6 M 95.84 0.14 0.16 — 0.05 0.05 99.4 7.88  9 M 12 M 18 M 24 MStorage condition: 40° C. Initial 100.62 — — — — 0.0 100.0 8.17  1 M96.17 — 0.25 0.10 0.16 0.11 99.0 8.05  2 M 95.58 0.72 0.36 0.18 0.210.14 97.7 7.89  3 M 92.89 1.13 0.47 0.25 0.35 0.13 96.9 7.86  6 M 85.662.30 0.57 0.45 0.75 0.16 94.3 7.75

TABLE 30 Stability profile of HCP Formulation #4 Description: Drugconcentration: 13.42%, pH 8.5 % % % % % % % Impurity 1 Impurity 2Impurity 3 Impurity 4 Hydrocortisone Peak pH of Duration Assay RRT 0.26RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 area formulation Storage condition:25° C. Initial 100.41 — — — — 0.0 100.0 8.54  3 M 95.95 — 0.14 — — 0.0499.7 8.30  6 M 95.36 0.19 0.23 — 0.06 0.03 99.3 8.06  9 M 12 M 18 M 24 MStorage condition: 40° C. Initial 100.41 — — — — 0.0 100.0 8.54  1 M96.94 — 0.31 0.12 0.10 0.08 99.0 8.27  2 M 94.39 0.80 0.44 0.21 0.120.09 98.0 8.07  3 M 92.66 1.20 0.52 0.30 0.22 0.09 97.2 8.08  6 M 88.672.42 0.63 0.55 0.55 0.12 94.4 7.88

TABLE 31 Stability profile of HCP Formulation #5 Description: Drugconcentration: 6.71%, pH 8.0 % % % % % % % Impurity 1 Impurity 2Impurity 3 Impurity 4 Hydrocortisone Peak pH of Duration Assay RRT 0.26RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 area formulation Storage condition:25° C. Initial 99.63 — — — — 0.0 100.0 8.02  3 M 88.39 — 0.12 — — 0.0699.7 7.99  6 M 92.41 0.12 0.19 — 0.06 0.10 99.3 7.76  9 M 12 M 18 M 24 MStorage condition: 40° C. Initial 99.63 — — — — 0.0 100.0 8.02  1 M91.10 — 0.29 0.10 0.10 0.15 99.0 7.88  2 M 88.86 0.93 0.55 0.16 0.230.20 97.5 7.79  3 M 87.25 1.37 0.71 0.22 0.42 0.17 86.3 7.78  6 M 79.673.11 1.16 0.35 0.84 0.22 92.6 7.64

TABLE 32 Stability profile of HCP Formulation #6 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Sodium sulfite % % % % % % %Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone Peak pH ofDuration Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 103.37 — — — — 0.0 99.98.34  3 M 101.28 — — — — 0.00 99.9 8.50  6 M 99.59 — — 0.07 0.06 0.0299.8 8.40  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial 103.37 —— — — 0.0 99.9 8.34  1 M 100.02 — — 0.29 — 0.07 99.5 8.44  2 M 99.71 — —0.45 0.13 0.07 99.2 8.41  3 M 99.46 — — 0.75 0.19 0.07 98.9 8.47  6 M95.26 0.06 — 1.16 0.26 0.06 98.2 8.46

TABLE 33 Stability profile of HCP Formulation #7 Description: Drugconcentration: 13.42%, pH 8.0, effect of Monothioglycerol % % % % % % %Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone Peak pH ofDuration Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 103.06 — — — — 0.0 100.08.56  3 M 98.87 — — 0.05 — 0.00 99.9 8.65  6 M 99.58 — — 0.09 — 0.0399.9 8.58  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial 103.06 —— — — 0.0 100.0 8.56  1 M 100.27 — — 0.27 — 0.07 99.7 8.59  2 M 101.01 —— 0.51 — 0.10 99.3 8.51  3 M 99.27 — — 0.84 — 0.12 98.9 8.49  6 M 97.99— — 1.36 — 0.12 98.2 8.58

TABLE 34 Stability profile of HCP Formulation #8A Description: Drugconcentration: 13.42%, pH 8.0, Effect of Ascorbic acid and unpouchedsample % % % % % % % Impurity 1 Impurity 2 Impurity 3 Impurity 4Hydrocortisone Peak pH of Duration Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT1.24 RRT 1.09 area formulation Storage condition: 25° C. Initial 99.92 —— — — 0.0 100.0 8.37  3 M 99.94 — — — 0.05 0.04 99.9 8.08  6 M 99.40 — —0.04 0.08 0.05 99.8 7.96  9 M 12 M 18 M 24 M Storage condition: 40° C.Initial 99.92 — — — — 0.0 100.0 8.37  1 M 99.04 — — 0.13 — 0.10 99.68.19  2 M 99.84 — — 0.16 0.15 0.14 99.5 7.94  3 M 99.41 — — 0.28 0.290.24 99.1 7.88  6 M 95.40 — — 0.46 0.71 0.46 97.9 7.72

TABLE 35 Stability profile of HCP Formulation #8B Description: Drugconcentration: 13.42%, pH 8.0, Effect of Ascorbic acid and pouched withNitrogen purging % % % % % % % Impurity 1 Impurity 2 Impurity 3 Impurity4 Hydrocortisone Peak pH of Duration Assay RRT 0.26 RRT 0.79 RRT 0.91RRT 1.24 RRT 1.09 area formulation Storage condition: 25° C. Initial99.92 — — — — 0.0 100.0 8.37  3 M 100.16 — — — 0.07 0.04 99.8 7.97  6 M98.25 — — 0.03 0.10 0.06 99.8 7.82  9 M 12 M 18 M 24 M Storagecondition: 40° C. Initial 99.92 — — — — 0.0 100.0 8.37  1 M 99.74 — —0.11 0.11 0.10 99.5 8.47  2 M 99.63 — — 0.18 0.17 0.16 99.4 7.94  3 M99.55 — — 0.25 0.28 0.22 99.1 7.90  6 M 98.84 — — 0.45 0.70 0.44 98.07.72

TABLE 36 Stability profile of HCP Formulation #8C Description: Drugconcentration: 13.42%, pH 8.0, Effect of Ascorbic acid and pouched with2 Oxygen scavengers. % % % % % % % Impurity 1 Impurity 2 Impurity 3Impurity 4 Hydrocortisone Peak pH of Duration Assay RRT 0.26 RRT 0.79RRT 0.91 RRT 1.24 RRT 1.09 area formulation Storage condition: 25° C.Initial 99.92 — — — — 0.0 100.0 8.37  3 M 101.20 — — — 0.05 0.04 99.98.12  6 M 100.06 — — 0.03 0.07 0.05 99.9 7.89  9 M 12 M 18 M 24 MStorage condition: 40° C. Initial 99.92 — — — — 0.0 100.0 8.37  1 M99.73 — — 0.11 — 0.10 99.6 8.06  2 M 99.96 — — 0.23 0.18 0.15 99.4 8.03 3 M 100.11 — — 0.37 0.30 0.21 99.0 8.00  6 M 97.27 — — 0.55 0.58 0.3198.3 7.93

TABLE 37 Stability profile of HCP Formulation #9 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Methoinine. % % % % % % %Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone Peak pH ofDuration Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 102.86 — — — — 0.0 100.08.61  3 M 97.89 0.05 — 0.04 0.06 0.00 99.7 8.38  6 M 98.37 0.07 — 0.060.08 0.02 99.6 8.26  9 M 12 M 18 M 24 M Storage condition: 40° C.Initial 102.86 — — — — 0.0 100.0 8.61  1 M 96.11 — — 0.22 0.34 0.05 99.48.19  2 M 99.09 0.05 — 0.39 0.14 0.07 99.0 8.29  3 M 97.52 0.06 — 0.560.24 0.08 98.7 8.29  6 M 95.08 0.07 — 0.95 0.42 0.10 97.6 8.16

TABLE 38 Stability profile of HCP Formulation #10 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Creatinine. % % % % % % %Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone Peak pH ofDuration Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 103.32 — — — — 0.0 100.08.11  3 M 95.68 — 0.03 — — 0.04 99.9 7.01  6 M 93.95 — 0.05 — — 0.0399.9 7.95  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial 103.32 —— — — 0.0 100.0 8.11  1 M 91.71 0.07 0.08 0.08 — 0.09 99.6 8.05  2 M101.45 0.11 0.10 0.11 — 0.09 99.5 7.82  3 M 93.59 0.27 0.13 0.17 0.070.12 98.8 7.85  6 M 90.78 0.44 0.14 0.30 0.15 0.13 97.8 7.75

TABLE 39 Stability profile of HCP Formulation #11 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Niacinamide. % % % % % Impurity1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone % Peak pH of Duration% Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 area formulationStorage condition: 25° C. Initial 100.15 — — — — 0.0 100.0 8.11  3 M95.69 — — — — 0.05 99.9 8.01  6 M 93.72 — 0.06 — — 0.05 99.8 7.95  9 M12 M 18 M 24 M Storage condition: 40° C. Initial 100.15 — — — — 0.0100.0 7.95  1 M 92.79 0.14 0.15 0.07 — 0.15 99.4 7.95  2 M 94.22 0.330.20 0.13 0.19 0.16 98.8 7.77  3 M 91.85 0.76 0.33 0.14 0.40 0.16 97.57.86  6 M 88.89 1.09 0.38 0.32 0.69 0.16 96.2 7.78

TABLE 40 Stability profile of HCP Formulation #12 Description: Drugconcentration: 13.42%, pH 8.0, Effect of 5% HP-β-cyclodextrin. % % % % %Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone % Peak pH ofDuration % Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 100.99 — — — — 0.0 100.08.1  3 M 98.38 — 0.08 — — 0.05 99.8 8.04  6 M 94.96 — 0.16 — 0.04 0.0599.5 7.92  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial 100.99 —— — — 0.0 100.0 8.1  1 M 91.91 0.17 0.18 0.07 — 0.10 99.3 7.98  2 M94.04 0.43 0.30 0.14 0.14 0.13 98.6 7.82  3 M 92.70 0.84 0.41 0.21 0.300.15 97.5 7.85  6 M 87.37 1.81 0.61 0.33 0.63 0.14 95.0 7.79

TABLE 41 Stability profile of HCP Formulation #13 Description: Drugconcentration: 13.42%, pH 8.0, Effect of 10% HP-β-cyclodextrin. % % % %% Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone % Peak pHof Duration % Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 99.99 — — — — 0.0 100.08.01  3 M 96.97 — 0.09 — — 0.05 99.8 8.00  6 M 95.41 0.08 0.15 — — 0.0699.5 7.90  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial 99.99 —— — — 0.0 100.0 8.01  1 M 94.62 0.15 0.19 0.08 — 0.13 99.2 8.02  2 M94.66 0.36 0.27 0.12 0.12 0.13 98.8 7.79  3 M 92.40 0.88 0.44 0.20 0.300.15 97.4 7.90  6 M 88.55 1.54 0.56 0.30 0.58 0.14 95.5 7.78

TABLE 42 Stability profile of HCP Formulation #14 Description: Drugconcentration: 13.42%, pH 8.0, Effect of Lactbionic acid. % % % % %Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone % Peak pH ofDuration % Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 100.34 — — — — 0.0 100.08.04  3 M 96.09 — 0.08 — — 0.05 99.8 8.00  6 M 94.21 0.10 0.15 — 0.050.05 99.5 7.87  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial100.34 — — — — 0.0 100.0 8.04  1 M 94.32 0.14 0.20 0.06 — 0.10 99.4 8.02 2 M 95.79 0.40 0.28 0.11 0.12 0.13 98.8 7.81  3 M 94.63 0.82 0.40 0.170.29 0.13 97.7 7.88  6 M 88.85 1.67 0.54 0.30 0.62 0.13 95.4 7.79

TABLE 43 Stability profile of HCP Formulation #15A Description: Drugconcentration: 13.42%, pH 8.0, unpouched sample. % % % % % Impurity 1Impurity 2 Impurity 3 Impurity 4 Hydrocortisone % Peak pH of Duration %Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 area formulationStorage condition: 25° C. Initial 102.24 — — — — 0.0 100.0 7.98  3 M95.80 — 0.09 — — 0.04 99.8 7.90  6 M 94.80 0.12 0.16 — 0.06 0.05 99.47.87  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial 102.24 — — —— 0.0 100.0 7.98  1 M 93.50 0.34 0.26 0.11 0.08 0.13 98.8 7.94  2 M93.67 0.98 0.44 0.22 0.33 0.15 97.4 7.90  3 M 91.42 1.11 0.46 0.23 0.400.15 96.9 7.81  6 M 87.07 2.06 0.58 0.38 0.72 0.16 94.7 7.79

TABLE 44 Stability profile of HCP Formulation #15B Description: Drugconcentration: 13.42%, pH 8.0, pouched with Nitrogen purging. % % % % %Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone % Peak pH ofDuration % Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 102.24 — — — — 0.0 100.07.98  3 M 96.23 — 0.08 — — 0.04 99.8 7.88  6 M 95.35 0.13 0.17 — 0.060.05 99.4 7.85  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial102.24 — — — — 0.0 100.0 7.98  1 M 94.57 0.21 0.20 0.05 0.03 0.11 99.27.93  2 M 95.28 0.83 0.41 0.18 0.28 0.13 97.7 7.94  3 M 91.77 0.89 0.440.21 0.34 0.15 97.4 7.83  6 M 88.69 1.88 0.54 0.35 0.65 0.16 95.1 7.84

TABLE 45 Stability profile of HCP Formulation #15C Description: Drugconcentration: 13.42%, pH 8.0, pouched with 2 Oxygen scavengers. % % % %% Impurity 1 Impurity 2 Impurity 3 Impurity 4 Hydrocortisone % Peak pHof Duration % Assay RRT 0.26 RRT 0.79 RRT 0.91 RRT 1.24 RRT 1.09 areaformulation Storage condition: 25° C. Initial 102.24 — — — — 0.0 100.07.98  3 M 93.75 — 0.07 — — 0.05 99.9 7.85  6 M 94.81 0.07 .012 — — 0.0799.6 7.75  9 M 12 M 18 M 24 M Storage condition: 40° C. Initial 102.24 —— — — 0.0 100.0 7.98  1 M 94.04 0.20 0.20 0.07 0.02 0.12 99.2 7.98  2 M94.34 0.58 0.27 0.19 0.21 0.24 98.2 7.96  3 M 92.25 0.57 0.27 0.21 0.260.27 98.2 7.82  6 M 90.92 1.02 0.24 0.37 0.66 0.39 96.7 7.81

TABLE 46 Summary of all HCP formulations after 6 M of storage at 25° C.and 40° C. % Assay value Drug Antioxidant or Packing of HCP Form, # pHconc. solublizing agent type 25° C. 40° C.  1 7.0 13.42 None — 95.3080.32  2 7.5 13.42 None — 95.80 86.72  3 8.0 13.42 None — 95.84 85.66  48.5 13.42 None — 95.36 88.67  5 8.0 6.71 None — 92.41 79.67  6 8.0 13.42Sodium Sulfite — 99.59 95.26  7 8.0 13.42 Monothioglycerol — 99.58 97.99 8A 8.0 13.42 Ascorbic acid Unpouched 99.40 95.40  8B 8.0 13.42 Ascorbicacid N₂ purging 98.25 98.84  8C 8.0 13.42 Ascorbic acid O₂ 100.06 97.27  scavenger  9 8.0 13.42 Methionine — 98.37 95.08 10 8.0 13.42Creatinine — 93.95 90.78 11 8.0 13.42 Niacinamide — 93.72 88.89 12 8.013.42 5% HP-β-CD — 94.96 87.37 13 8.0 13.42 10% HP-β-CD — 95.41 88.55 148.0 13.42 Lactobionic acid — 94.21 88.85 15A 8.0 13.42 None Unpouched94.80 87.07 15B 8.0 13.42 None N₂ purging 95.35 86.69 15C 8.0 13.42 NoneO₂ 94.81 90.92 scavenger

Without wishing to be bound by any particular theory, and afterstability analysis of all HCP formulations for 6 months of storage at25° C. and 40° C., HCP F #7 seems to be the most stable formulation. Itcontains 0.5% w/v Monothioglycerol as an antioxidant. Monothioglycerolis a liquid excipient.

Example 2: Exemplary Hydrocortisone Injection Formulation

Composition FDA inactive Composition per unit dose, ingredientIngredients Function per 1 mL 2 mL database limit Hydrocortisone Active67.1 mg (50 mg 134.2 mg (100 mg — sodium phosphate ingredienthydrocortisone) hydrocortisone) Monobasic Buffer 1.0 mg 2.0 mg 1.2% w/v,IM sodium phosphate agent anhydrous Dibasic sodium Buffer 10.9 mg 21.8mg 1.75% w/v, IM phosphate agent anhydrous Disodium edetate Chelating0.2 mg 0.4 mg 10% w/v, IM agent Monothioglycerol Antioxidant 5.0 mg 10.0mg 0.5% w/v, IM Sodium pH adjustor Q.S. pH Q.S pH — hydroxide/HCl (appr8.0) (appr 8.0) Water Solvent Q.S. to 1 mL Q.S. to 1 mL —

Example 3: Stability Data for Example Formulations to EvaluateAlternative Antioxidants

Total Impurities (% area), 40° C. Time F#3, F#6, F#7, F#8, F#9, (mon)EDTA/Rongalite EDTA/sulfite EDTA/MTG EDTA/ascorbic acid EDTA/methionine0 0.00% 0.09% 0.00% 0.00% 0.00% 1 0.97% 0.53% 0.35% 0.42% 0.50% 2 2.14%0.77% 0.74% 0.52% 0.98% 3 3.05% 1.07% 1.13% 0.93% 1.31% 6 5.72% 1.80%1.78% 2.08% 2.42%

Also as shown in FIG. 4 which illustrates the stability of twoformulations (#3 and #7) over 6 months.

Total Impurities (% area), 25° C. Time F#3, F#6, F#7, F#8, F#9, (mon)EDTA/Rongalite EDTA/sulfite EDTA/MTG EDTA/ascorbic acid EDTA/methionine0 0.00% 0.09% 0.00% 0.00% 0.00% 3 0.20% 0.04% 0.06% 0.15% 0.31% 6 0.61%0.21% 0.12% 0.17% 0.42%

Stability Data for Example Formulations to the third additive,Creatinine

Total Impurities (% area), 40° C. F#10, EDTA/ Time F#3, EDTA/ Rongalite/(mon) Rongalite Creatinine 0 0.00% 0.00% 1 0.97% 0.38% 2 2.14% 0.48% 33.05% 1.20% 6 5.72% 2.22%

FIG. 5 illustrates the stability of two formulations (#3 and #10) over 6months.

Total Impurities (% area), 25° C. F#10, EDTA/ Time F#3, EDTA/ Rongalite/(mon) Rongalite Creatinine 0 0.00% 0.00% 3 0.20% 0.09% 6 0.61% 0.12%

Example 4: Formulation Concentrations

Formulation: Equivalent to: Equivalent to: Equivalent to: Equivalent to:50 mg/ml 100 mg/ml 100 mg/ml 100 mg/ml Component hydrocortisonehydrocortisone hydrocortisone hydrocortisone Hydrocortisone 67.1 mg6.71% 134.2 mg 13.42% 6710.0 mg 13.42%  2,013.0 g 13.42% sodiumphosphate Monobasic sodium  1.0 mg 0.10%  1.0 mg  0.10%  50.0 mg  0.10%   19.5 g⁽¹⁾  0.13%⁽¹⁾ phosphate Dibasic sodium 10.9 mg 1.09%  10.9 mg 1.09%  545.0 mg  1.09%   205.5 g ⁽²⁾  1.37% ⁽²⁾ phosphate Disodium EDTA 0.2 mg 0.02%  0.2 mg  0.02%  10.0 mg  0.02%    3.0 g  0.02%Monothioglycerol  5.0 mg 0.50%  5.0 mg  0.50%  250.0 mg  0.50%    75.0 g 0.50% Sodium hydroxide Water (Q.S.) 1 mL 1 mL 50 mL 15,900.0 g ⁽³⁾⁽¹⁾Monobasic sodium phosphate dihydrate ⁽²⁾ Dibasic sodium phosphatedihydrate ⁽³⁾ Equivalent to 15 Liter

Example 5: Stability Data

Release (Time Stability Time (months) Time (months) Time (months)Analysis zero) limits acceptance limits 0 3 6 Appearance & pH AppearanceClear colorless Clear colorless Clear colorless Clear colorless Clearcolorless of Solution to yellowish to yellowish to yellowish toyellowish to yellowish solution in a 2.25 solution in a 2.25 solution ina 2.25 solution in a 2.25 solution in a 2.25 mL glass syringe mL glasssyringe mL glass syringe mL glass syringe mL glass syringe with greystopper with grey stopper with grey stopper with grey stopper with greystopper pH 7.5-8.5 7.5-8.5 8.0 8.0 8.0 Assay & Impurities Assay of127.5-140.9 (mg/mL) 120.8-147.6 (mg/mL) 137.2 139.0 136.6 HydrocortisoneSodium Phosphate Assay of 95-105% of label claim 95-110% of label claim102.2 103.6 101.8 Hydrocortisone Equivalent Specified Impurity, %Hydrocortisone ≤0.5% ≤2.0% <0.05% <0.05%  0.05% RRT 0.91 ≤0.1% ≤0.5%<0.05% <0.05% <0.05% Single Unspecified Impurity, % RRT 0.23 ≤0.1% ≤0.2%—  0.05%  0.07% RRT 1.03 ≤0.1% ≤0.2%  0.05% <0.05% <0.05% RRT 1.16 ≤0.1%≤0.2% — —  0.05% Sum of Impurities, % ≤1.0% ≤3.0%  0.05%  0.05%  0.16%Sub-Visible Particles ≥10 μm ≤6000 part. Per Container ≤6000 part. PerContainer 433 95 200 ≥25 μm ≤600 part. Per Container ≤600 part. PerContainer 4 1 2 Uniformity of dosage Volume in container 1.0-1.2 mL1.0-1.2 mL Complies, Complies, To be added Individual deliveredIndividual delivered 1.) 1.5 1.) 1.06 volume (mL): volume (mL): 2.) 1.052.) 1.06 To be reported To be reported 3.) 1.05 3.) 1.05 4.) 1.05 4.)1.07 5.) 1.05 5.) 1.06 Uniformity of Acceptance value Acceptance valueComplies after Complies after To be added dosage units (AV) for 10 (AV)for 10 first step, first step, dosage units ≤15.0, dosage units ≤15.0,Acceptance Acceptance if AV >15.0, if AV >15.0, value = 2.0, value =3.1, test the next 20 test the next 20 Average Average dosage units, AVdosage units, AV Volume = Volume = for 30 dosage for 30 dosage 1.05 mL1.05 mL units ≤15.0, No units ≤15.0, No individual content individualcontent of any dosage of any dosage unit is less than unit is less than[0.75M] or more [0.75M] or more than [1.25M], Average than [1.25M],Average volume: To volume: To be reported. be reported. Microbiologicaltests Sterility Sterile Sterile Sterile Not tested Not tested BaterialEndotoxins ≤1.25 EU/mg ≤1.25 EU/mg ≤1.25 EU/mg Not tested Not testedhydrocortisone hydrocortisone hydrocortisone

Example 6

One unknown impurity peak (RRT 0.91) in hydrocortisone phosphate productwas purified via preparative HPLC and characterized by LCMS, HPLC andNMR. Its structure was tentatively proposed as phosphate migrationisomer of hydrocortisone phosphate.¶

While certain embodiments of the present invention have been describedand/or exemplified above, various other embodiments will be apparent tothose skilled in the art from the foregoing disclosure. The presentinvention is, therefore, not limited to the particular embodimentsdescribed and/or exemplified, but is capable of considerable variationand modification without departure from the scope and spirit of theappended claims.

1. An aqueous pharmaceutical formulation comprising from about 50 toabout 150 mg/mL hydrocortisone sodium phosphate, from about 2.5 to about12.5 mg/mL monothioglycerol, and water.
 2. The aqueous pharmaceuticalformulation of claim 1, comprising from about 50 to about 60 mg/mLhydrocortisone sodium phosphate, from about 60 to about 70 mg/mLhydrocortisone sodium phosphate, or from about 70 to about 80 mg/mLhydrocortisone sodium phosphate.
 3. The aqueous pharmaceuticalformulation of claim 1, comprising from about 60 to about 65 mg/mLhydrocortisone sodium phosphate, or from about 65 to about 70 mg/mLhydrocortisone sodium phosphate.
 4. The aqueous pharmaceuticalformulation of claim 1, comprising from about 120 to about 130 mg/mLhydrocortisone sodium phosphate, from about 130 to about 140 mg/mLhydrocortisone sodium phosphate, or from about 140 to about 150 mg/mLhydrocortisone sodium phosphate.
 5. The aqueous pharmaceuticalformulation of claim 1, comprising from about 130 to about 135 mg/mLhydrocortisone sodium phosphate, or from about 135 to about 140 mg/mLhydrocortisone sodium phosphate.
 6. The aqueous pharmaceuticalformulation of claim 1, comprising about 50 mg/mL hydrocortisone sodiumphosphate, about 55 mg/mL hydrocortisone sodium phosphate, about 60mg/mL hydrocortisone sodium phosphate, about 65 mg/mL hydrocortisonesodium phosphate, about 70 mg/mL hydrocortisone sodium phosphate, about75 mg/mL hydrocortisone sodium phosphate, about 80 mg/mL hydrocortisonesodium phosphate, about 85 mg/mL hydrocortisone sodium phosphate, about90 mg/mL hydrocortisone sodium phosphate, about 95 mg/mL hydrocortisonesodium phosphate, about 100 mg/mL hydrocortisone sodium phosphate, about105 mg/mL hydrocortisone sodium phosphate, about 110 mg/mLhydrocortisone sodium phosphate, about 115 mg/mL hydrocortisone sodiumphosphate, about 120 mg/mL hydrocortisone sodium phosphate, about 125mg/mL hydrocortisone sodium phosphate, about 130 mg/mL hydrocortisonesodium phosphate, about 135 mg/mL hydrocortisone sodium phosphate, about140 mg/mL hydrocortisone sodium phosphate, about 145 mg/mLhydrocortisone sodium phosphate, or about 150 mg/mL hydrocortisonesodium phosphate.
 7. The aqueous pharmaceutical formulation of claim 1,comprising about 60 mg/mL hydrocortisone sodium phosphate, about 61mg/mL hydrocortisone sodium phosphate, about 62 mg/mL hydrocortisonesodium phosphate, about 63 mg/mL hydrocortisone sodium phosphate, about64 mg/mL hydrocortisone sodium phosphate, about 65 mg/mL hydrocortisonesodium phosphate, about 66 mg/mL hydrocortisone sodium phosphate, about67 mg/mL hydrocortisone sodium phosphate, about 68 mg/mL hydrocortisonesodium phosphate, about 69 mg/mL hydrocortisone sodium phosphate, orabout 70 mg/mL hydrocortisone sodium phosphate.
 8. The aqueouspharmaceutical formulation of claim 1, comprising about 67 mg/mLhydrocortisone sodium phosphate, about 67.1 mg/mL hydrocortisone sodiumphosphate, about 67.2 mg/mL hydrocortisone sodium phosphate, about 67.3mg/mL hydrocortisone sodium phosphate, about 67.4 mg/mL hydrocortisonesodium phosphate, about 67.5 mg/mL hydrocortisone sodium phosphate,about 67.6 mg/mL hydrocortisone sodium phosphate, about 67.7 mg/mLhydrocortisone sodium phosphate, about 67.8 mg/mL hydrocortisone sodiumphosphate, about 67.9 mg/mL hydrocortisone sodium phosphate, or about 68mg/mL hydrocortisone sodium phosphate.
 9. The aqueous pharmaceuticalformulation of claim 1, comprising about 130 mg/mL hydrocortisone sodiumphosphate, about 131 mg/mL hydrocortisone sodium phosphate, about 132mg/mL hydrocortisone sodium phosphate, about 133 mg/mL hydrocortisonesodium phosphate, about 134 mg/mL hydrocortisone sodium phosphate, about135 mg/mL hydrocortisone sodium phosphate, about 136 mg/mLhydrocortisone sodium phosphate, about 137 mg/mL hydrocortisone sodiumphosphate, about 138 mg/mL hydrocortisone sodium phosphate, about 139mg/mL hydrocortisone sodium phosphate, or about 140 mg/mL hydrocortisonesodium phosphate.
 10. The aqueous pharmaceutical formulation of claim 1,comprising about 134 mg/mL hydrocortisone sodium phosphate, about 134.1mg/mL hydrocortisone sodium phosphate, about 134.2 mg/mL hydrocortisonesodium phosphate, about 134.3 mg/mL hydrocortisone sodium phosphate,about 134.4 mg/mL hydrocortisone sodium phosphate, about 134.5 mg/mLhydrocortisone sodium phosphate, about 134.6 mg/mL hydrocortisone sodiumphosphate, about 134.7 mg/mL hydrocortisone sodium phosphate, about134.8 mg/mL hydrocortisone sodium phosphate, about 134.9 mg/mLhydrocortisone sodium phosphate, or about 135 mg/mL hydrocortisonesodium phosphate.
 11. The aqueous pharmaceutical formulation of claim 1,comprising from about 2.5 to about 3.5 mg/mL monothioglycerol, fromabout 3.5 to about 4.5 mg/mL monothioglycerol, from about 4.5 to about5.5 mg/mL monothioglycerol, from about 5.5 to about 6.5 mg/mLmonothioglycerol, from about 6.5 to about 7.5 mg/mL monothioglycerol,from about 7.5 to about 8.5 mg/mL monothioglycerol, from about 8.5 toabout 9.5 mg/mL monothioglycerol, from about 9.5 to about 10.5 mg/mLmonothioglycerol, from about 10.5 to about 11.5 mg/mL monothioglycerol,or from about 11.5 to about 12.5 mg/mL monothioglycerol.
 12. The aqueouspharmaceutical formulation of claim 1, comprising from about 4 to about4.25 mg/mL monothioglycerol, from about 4.25 to about 4.5 mg/mLmonothioglycerol, from about 4.5 to about 4.75 mg/mL monothioglycerol,from about 4.75 to about 5 mg/mL monothioglycerol, from about 5 to about5.25 mg/mL monothioglycerol, from about 5.25 to about 5.5 mg/mLmonothioglycerol, from about 5.5 to about 5.75 mg/mL monothioglycerol,or from about 5.75 to about 6 mg/mL monothioglycerol.
 13. The aqueouspharmaceutical formulation of claim 1, comprising from about 9 to about9.25 mg/mL monothioglycerol, from about 9.25 to about 9.5 mg/mLmonothioglycerol, from about 9.5 to about 9.75 mg/mL monothioglycerol,from about 9.75 to about 10 mg/mL monothioglycerol, from about 10 toabout 10.25 mg/mL monothioglycerol, from about 10.25 to about 10.5 mg/mLmonothioglycerol, from about 10.5 to about 10.75 mg/mL monothioglycerol,or from about 10.75 to about 11 mg/mL monothioglycerol.
 14. The aqueouspharmaceutical formulation of claim 1, comprising about 4.5 mg/mLmonothioglycerol, about 4.6 mg/mL monothioglycerol, about 4.7 mg/mLmonothioglycerol, about 4.8 mg/mL monothioglycerol, about 4.9 mg/mLmonothioglycerol, about 5 mg/mL monothioglycerol, about 5.1 mg/mLmonothioglycerol, about 5.2 mg/mL monothioglycerol, about 5.3 mg/mLmonothioglycerol, about 5.4 mg/mL monothioglycerol, or about 5.5 mg/mLmonothioglycerol.
 15. The aqueous pharmaceutical formulation of claim 1,comprising about 9.5 mg/mL monothioglycerol, about 9.6 mg/mLmonothioglycerol, about 9.7 mg/mL monothioglycerol, about 9.8 mg/mLmonothioglycerol, about 9.9 mg/mL monothioglycerol, about 10 mg/mLmonothioglycerol, about 10.1 mg/mL monothioglycerol, about 10.2 mg/mLmonothioglycerol, about 10.3 mg/mL monothioglycerol, about 10.4 mg/mLmonothioglycerol, or about 10.5 mg/mL monothioglycerol.
 16. The aqueouspharmaceutical formulation of claim 1, further comprising from about 0.5to about 2.5 mg/mL monobasic sodium phosphate, from about 5 to about 25mg/mL dibasic sodium phosphate, and from about 0.1 to about 1 mg/mLdisodium EDTA. 17-18. (canceled)
 19. The aqueous pharmaceuticalformulation of claim 1, wherein the pharmaceutical formulation has a pHfrom about 7.5 to about 9.5.
 20. (canceled)
 21. The aqueouspharmaceutical formulation of claim 1, wherein the formulation comprisesfrom no impurities to less than, or no more than 0.05% impurities uponformulation.
 22. The aqueous pharmaceutical formulation of claim 1,wherein the formulation comprises from no impurities to less than, or nomore than 0.07% impurities upon storage at 25° C. for about 3 months.23-25. (canceled)
 26. The aqueous pharmaceutical formulation of claim 1,wherein upon storage at 40° C. for about 1 month, the formulationcomprises from no impurities to less than, or no more than 0.35%impurities. 27-50. (canceled)